Neuroactive 13, 17-substituted steroids as modulators for GABA type-A receptors

ABSTRACT

The present disclosure is generally directed to neuroactive 13,17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority benefit of U.S. Provisional PatentApplication Ser. No. 61/771,350, filed on Mar. 1, 2013, the entirecontent of which is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with Government support under NIH Grant#GM047969, awarded by the National Institute of Health. The Governmenthas certain rights in the invention.

BACKGROUND OF THE DISCLOSURE

The present disclosure is generally directed to novel compounds havingutility as an anesthetic and/or in the treatment of disorders relatingto GABA function and activity. More specifically, the present disclosureis directed to steroids having a 13,17-substituted tetracyclic structurethat are neuroactive and suitable for use as an anesthetic, as well aspharmaceutically acceptable salts thereof, and pharmaceuticalcompositions containing them.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitterof the central nervous system. GABA activates two types of receptors,the inotropic GABA_(A) and the metabotropic GABA_(B) receptor.Activation of the GABA_(B) receptor by GABA causes hyperpolarization anda resultant inhibition of neurotransmitter release. The GABA_(A)receptor subtype regulates neuronal excitability and rapid mood changes,such as anxiety, panic, and stress response. GABA_(A) receptors arechloride ion channels; as a result, activation of the receptor inducesincreased inward chloride ion flux, resulting in membranehyperpolarization and neuronal inhibition. Drugs that stimulate GABA_(A)receptors, such as benzodiazepines and barbiturates, have anticonvulsiveeffects (by reducing neuronal excitability and raising the seizurethreshold), as well as anxiolytic and anesthetic effects.

The effect of certain steroids on GABA_(A) receptors has beenwell-established. As a result, researchers continue to pursue thediscovery and synthesis of neuroactive steroids that may act asanesthetics and/or that may serve to provide treatment for disordersrelated to GABA function. For example, it is now widely accepted thatthe intravenous anesthetic alphaxalone (Compound A, below) causesgeneral anesthesia in humans because it allosterically increaseschloride currents mediated by GABA acting at GABA_(A) receptors in thebrain. However, the various structural features that enable thiscompound to function in the way it does have, to-date, not been fullyunderstood. For example, in contrast to alphaxalone, Δ¹⁶-alphaxalone(Compound B, below), has been observed to have greatly diminishedallosteric activity at GABA_(A) receptors and is not used as anintravenous general anesthetic in humans.

The difference in performance of these two compounds, which some haveattributed to the presence of the carbon-carbon double bond in theD-ring, has attracted the attention of many researchers. In fact,recently, it was determined that the effect this double bond has onanesthetic activity may depend on the group attached at C-17 on theD-ring. (See Bandyopadhyaya, A. K., et al., “Neurosteroid analogues. 15.A comparative study of the anesthetic and GABAergic actions ofalphaxalone, Δ¹⁶-alphaxalone and their corresponding 17-carbonitrileanalogues. Bioorg. Med. Chem. Lett., 20: 6680-4 (2010).)

In addition to anesthetic properties, neuroactive steroids may be usedto treat disorders related to GABA function. For example, neuroactivesteroids, such as progesterone, may be used as sedative-hypnotics,exhibiting benzodiazepine-like actions, inducing reduced sleep latencyand increased non-REM sleep with only small changes in slow wave and REMsleep. Further, drugs that enhance GABA responses are often used totreat anxiety in humans. Thus, it might be expected thatGABA-potentiating steroids would exhibit anxiolytic effects. Neuroactivesteroids may also be used to treat depression, given that accumulatingevidence suggests that patients with major depression have decreasedlevels of GABAergic neurosteroids and that certain treatments fordepression alter levels of these steroids. Although GABA is nottypically thought to play a critical role in the biology of depression,there is evidence that low GABAergic activity may predispose one to mooddisorders. Finally, inhibition of NMDA receptors and enhancement ofGABA_(A) receptors appear to play important roles in mediating the acuteeffects of ethanol in the nervous system, while related studies suggestthat GABAergic neurosteroids may be involved in some of thepharmacological effects of ethanol and that neuroactive steroids may beuseful in treating ethanol withdrawal.

In view of the foregoing, it is clear that there are a number ofpotentially advantageous uses for neurosteroids. As a result, there is acontinuing need for the further synthesis and understanding of newneuroactive steroids, particularly those having utility as an anestheticand/or in the treatment of a disorder relating to GABA function andactivity.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure is directed to a compound having astructure of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

R₁ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₂ is H, optionally substituted C₁-C₄ alkoxy, aryloxy, optionallysubstituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, or—O—C(O)—R_(x), where R_(x) is optionally substituted C₁-C₂₀ alkyl;

R₃ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted alkynyl, cyclopropyl, orC(O)R_(y), where R_(y) is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl;

R₄ is optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, optionally substituted cyclopropyl, or C(O)R_(z), where R_(z)is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl;

R₅ is H, ═O, or OR_(v), where R_(v) is H, optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, optionally substitutedC₂-C₄ alkynyl, or optionally substituted aryl;

R₆ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₇ is H, optionally substituted C₁-C₄ alkoxy, aryloxy, morpholinyl,optionally substituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄alkynoxy, or —O—C(O)—R_(w), where R_(w) is optionally substituted C₁-C₂₀alkyl;

R₈ is, when present, H, C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl;

R₉ is H or C(O)R_(u), where R_(u) is optionally substituted C₁-C₂₀alkyl, optionally substituted C₂-C₂₀ alkenyl, or optionally substitutedC₂-C₂₀ alkynyl; and,

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between C₄-C₅ or C₅-C₆, with the proviso that when present, theC₅—H substituent is not present.

The present disclosure is still further directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of one or moreof the above-noted steroids or pharmaceutically acceptable saltsthereof, and optionally a pharmaceutically acceptable carrier. Thepresent disclosure also provides kits comprising steroids, saltsthereof, and/or pharmaceutical compositions thereof.

The present disclosure further provides methods of inducing anesthesiain a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of one or more of theabove-noted steroids, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof.

The present disclosure further provides methods of treating disordersrelated to GABA function in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of one or more of the above-noted steroids, or pharmaceuticallyacceptable salts thereof, or a pharmaceutical composition thereof. Incertain embodiments, the disorder is selected from the group consistingof insomnia, mood disorders, convulsive disorders, Fragile X syndrome,anxiety, or symptoms of ethanol withdrawal.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In accordance with the present disclosure, it has been discovered thatcompounds having certain 13,17-substituted steroid structures areneuroactive and are also suitable for use as anesthetics and in thetreatment of disorders associated with GABA function, as well aspharmaceutically acceptable salts thereof. The compounds may be used,for example, as an effective continuous infusion sedative fornon-surgical procedures (e.g., colonoscopy). The compounds also offeradvantages over anesthetics known in the art, such as a lower likelihoodfor bacterial contamination, as well as an improved relationship withsolubilizing agents.

1. Steroid Structure

Generally speaking, the steroid of the present disclosure has atetracyclic, fused ring structure, such as a cyclopenta[a]phenanthrenering system (an embodiment of which is illustrated and discussed ingreater detail below), wherein the C₃-position of the A ring has ahydroxyl or an ester substituent in the alpha configuration, the C₁₃position has a substituent attached thereto in the beta configurationselected from the group consisting of optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, optionally substitutedcyclopropyl, and C(O)R_(z), where R_(z) is C₁-C₄ alkyl, C₂-C₄ alkenyl orC₂-C₄ alkynyl; and the C₁₇-position of the D ring has a substituentattached thereto in the beta configuration selected from the groupconsisting of H, optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted alkynyl, cyclopropyl,and C(O)R_(y), where R_(y) is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄alkynyl.

More particularly, however, the present disclosure is directed, incertain embodiments, to a steroid having the structure of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

R₁ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₂ is H, optionally substituted C₁-C₄ alkoxy, aryloxy, optionallysubstituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, or—O—C(O)—R_(x), where R_(x) is optionally substituted C₁-C₂₀ alkyl;

R₃ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted alkynyl, cyclopropyl, orC(O)R_(y), where R_(y) is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl;

R₄ is optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, optionally substituted cyclopropyl, or C(O)R_(z), where R_(z)is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl;

R₅ is H, ═O, or OR_(v), where R_(v) is H, optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, optionally substitutedC₂-C₄ alkynyl, or optionally substituted aryl;

R₆ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₇ is H, optionally substituted C₁-C₄ alkoxy, aryloxy, morpholinyl,optionally substituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄alkynoxy, or —O—C(O)—R_(w), where R_(w) is optionally substituted C₁-C₂₀alkyl;

R₈ is, when present, H, C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl;

R₉ is H or C(O)R_(u), where R_(u) is optionally substituted C₁-C₂₀alkyl, optionally substituted C₂-C₂₀ alkenyl, or optionally substitutedC₂-C₂₀ alkynyl; and,

- - - denotes an optional, additional C—C bond, resulting in either aC═C bond between C₄-C₅ or C₅-C₆, with the proviso that when present, theC₅—H substituent is not present.

As generally defined above, R₁ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₁ is H. R₁ is in the betaconfiguration.

As generally defined above, R₂ is H, optionally substituted C₁-C₄alkoxy, aryloxy, optionally substituted C₂-C₄ alkenoxy, optionallysubstituted C₂-C₄ alkynoxy, or —O—C(O)—R_(x), where R_(x) is optionallysubstituted C₁-C₂₀ alkyl. In certain embodiments, R_(x) is optionallysubstituted C₁-C₁₅ alkyl, C₁-C₁₀ alkyl, or C₁-C₄ alkyl. In a preferredembodiment, R₂ is H. In another preferred embodiment, R₂ is alkoxy(e.g., —OCH₃). R₂ is in the beta configuration.

As generally defined above, R₃ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, optionally substituted alkynyl,cyclopropyl, or C(O)R_(y), where R_(y) is C₁-C₄ alkyl, C₂-C₄ alkenyl orC₂-C₄ alkynyl. In certain embodiments, R₃ is —CH═CH₂. In other certainembodiments, R₃ is ethyl. In yet other certain embodiments, R₃ isC(O)CH₃. In certain embodiments, R₃ is hydroxyl alkyl. In a preferredembodiment, R₃ is C(OH)CH₃. In yet another preferred embodiment, R₃ isCH₂(OH). In other certain embodiments, R₃ is haloalkyl. In a preferredembodiment, R₃ is CH₂Cl. R₃ is in the beta configuration.

As generally defined above, R₄ is optionally substituted C₂-C₄ alkenyl,optionally substituted C₂-C₄ alkynyl, optionally substitutedcyclopropyl, or C(O)R_(z), where R_(z) is C₁-C₄ alkyl, C₂-C₄ alkenyl orC₂-C₄ alkynyl. In certain embodiments, R₄ is —CH═CH₂. In other certainembodiments, R₄ is C(O)CH₃. R₄ is in the beta configuration.

As generally defined above, R₅ is H, ═O, or OR_(v), where R_(v) is H,optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, optionally substituted C₂-C₄ alkynyl, or optionally substitutedaryl. In a preferred embodiment, R₅ is H. In another preferredembodiment, R₅ is alkoxy (e.g., —OCH₃). R₅ can be in either the betaconfiguration or the alpha configuration.

As generally defined above, R₆ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl. In a preferred embodiment, R₆ is methyl. In another preferredembodiment, R₆ is substituted alkyl, and more particularly isalkoxy-substituted alkyl (e.g., —CH₂OCH₃). R₆ is in the betaconfiguration.

As generally defined above, R₇ is H, optionally substituted C₁-C₄alkoxy, aryloxy, morpholinyl, optionally substituted C₂-C₄ alkenoxy,optionally substituted C₂-C₄ alkynoxy, or —O—C(O)—R_(w), where R_(w) isoptionally substituted C₁-C₂₀ alkyl. In certain embodiments, R_(w) isoptionally substituted C₁-C₁₅ alkyl, C₁-C₁₀ alkyl, or C₁-C₄ alkyl. In apreferred embodiment, R₇ is H. In another preferred embodiment, R₇ isalkoxy (e.g., —OCH₃). R₇ is in the beta configuration.

As generally defined above, R₈, when present (e.g., when R₅ is not ═O),is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl. In a preferredembodiment, R₈ is H.

As generally defined above, R₉ is H or C(O)R_(u), where R_(u) isoptionally substituted C₁-C₂₀ alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀ alkynyl. In certainembodiments, R_(u) is optionally substituted C₁-C₁₅ alkyl, C₁-C₁₀ alkyl,or C₁-C₄ alkyl. In other certain embodiments, R_(u) is optionallysubstituted C₁-C₁₅ alkenyl, C₁-C₁₀ alkenyl, or C₁-C₄ alkenyl. In yetother certain embodiments, R_(u) is optionally substituted C₁-C₁₅alkynyl, C₁-C₁₀ alkynyl, or C₁-C₄ alkynyl. In a preferred embodiment, R₉is H. The OR₉ substituent is in the alpha configuration.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in either a C═C bond between C₄-C₅ or C₅-C₆, with theproviso that when present, the C₅—H substituent is not present. Incertain embodiments, the additional C—C bond is absent, and the hydrogenat C₅ is in the alpha or beta configuration. In a preferred embodiment,the additional C—C bond is absent, and the hydrogen at C₅ is in thealpha configuration. In certain embodiments, - - - denotes an additionalC—C bond, resulting in a C═C bond between C₄-C₅. In certainembodiments, - - - denotes an additional C—C bond, resulting in a C═Cbond between C₅-C₆.

It is to be noted that the present disclosure contemplates and isintended to encompass all of the various combinations and permutations(i.e., combinations of substituent options, locations and stereochemicalconfigurations) possible here.

For example, in various embodiments, compounds of the present disclosurehave the formula of (I-a):

wherein:

R₃ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted alkynyl, cyclopropyl, orC(O)R_(y), where R_(y) is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl;and,

R₄ is optionally substituted C₂-C₄ alkenyl, optionally substituted C₂-C₄alkynyl, optionally substituted cyclopropyl, or C(O)R_(z), where R_(z)is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl.

As generally defined above in Formula (I-a), R₃ is H, optionallysubstituted C_(r) C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted alkynyl, cyclopropyl, or C(O)R_(y), where R_(y)is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl. In certain embodiments,R₃ is —CH═CH₂. In other certain embodiments, R₃ is ethyl. In yet othercertain embodiments, R₃ is C(O)CH₃. In certain embodiments, R₃ ishydroxyl alkyl. In a preferred embodiment, R₃ is C(OH)CH₃. In yetanother preferred embodiment, R₃ is CH₂(OH). In other certainembodiments, R₃ is haloalkyl. In a preferred embodiment, R₃ is CH₂Cl. R₃is in the beta configuration.

As generally defined above in Formula (I-a), R₄ is optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl,optionally substituted cyclopropyl, or C(O)R_(z), where R_(z) is C₁-C₄alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl. In certain embodiments, R₄ is—CH═CH₂. In other certain embodiments, R₄ is C(O)CH₃. R₄ is in the betaconfiguration.

Accordingly, as noted, the steroid of Formulas (I) and (I-a) mayencompass a number of various structures in accordance with the presentdisclosure, including all of the various combinations and permutations(i.e., combinations of substituent options, locations and stereochemicalconfigurations) possible here

Exemplary compounds of Formula (I) include, but are not limited to:

and pharmaceutically acceptable salts thereof.

In this regard it is to be noted that the structures provided above areof various exemplary embodiments. As such, they should not be viewed ina limiting sense.

3. Methods of Preparation and Pharmaceutical Compositions

It is to be noted that the compounds or steroids of the presentdisclosure, may in various embodiments be prepared or used in accordancewith means generally known in the art. For example, in certainembodiments, the steroids of the present disclosure may be prepared orused in a pharmaceutically acceptable salt form. Suitable salt formsinclude, for example, citrate or chloride salt forms.

In various embodiments of the present disclosure, a pharmaceuticalcomposition is disclosed that may comprise a steroid or a combination oftwo or more thereof in accordance with the formulas of the presentdisclosure. The compounds or steroids of the present disclosure, as wellas the various salt forms and other pharmaceutically acceptable forms,e.g., solvates and/or hydrates of compounds described herein, andpharmaceutical compositions containing them, may in general be preparedusing methods and techniques known in the art, and/or as described inthe Examples provided herein.

Without wishing to be bound by any particular theory, the compounds orsteroids of the present disclosure are useful for potentiating GABA atGABA_(A) receptors thereby inducing anesthesia or treating disordersrelated to GABA function (e.g., insomnia, mood disorders, Fragile Xsyndrome, convulsive disorders, anxiety disorders, or symptoms ofethanol withdrawal) in a subject, e.g., a human subject, and arepreferably administered in the form of a pharmaceutical compositioncomprising an effective amount of a compound of the instant disclosureand optionally a pharmaceutically or pharmacologically acceptablecarrier.

In one aspect, provided is a method of inducing anesthesia in a subjectin need thereof, the method comprising administering to the subject atherapeutically effective amount of one or more of the above-notedsteroids or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof.

In another aspect, provided is a method of treating disorders related toGABA function in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of oneor more of the above-noted steroids or pharmaceutically acceptable saltsthereof, or a pharmaceutical composition thereof. In certainembodiments, the disorder is selected from the group consisting ofinsomnia, mood disorders, convulsive disorders, Fragile X syndrome,anxiety, or symptoms of ethanol withdrawal.

In one embodiment of the present disclosure, a therapeutically effectiveamount of compound is from about 5 mg/kg to about 20 mg/kg, about 5mg/kg to about 18 mg/kg, about 5 mg/kg to about 16 mg/kg, about 5 mg/kgto about 14 mg/kg, about 5 mg/kg to about 12 mg/kg, about 5 mg/kg toabout 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6 mg/kg to about9 mg/kg, about 7 mg/kg to about 9 mg/kg, or about 8 mg/kg to about 16mg/kg. In certain embodiments, a therapeutically effective amount of thecompound is about 8 mg/kg. It will be appreciated that dose ranges asdescribed herein provide guidance for the administration of providedpharmaceutical compositions to an adult. The amount to be administeredto, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, identity of the particularcompound(s), mode of administration, and the like. The desired dosagecan be delivered three times a day, two times a day, once a day, everyother day, every third day, every week, every two weeks, every threeweeks, or every four weeks. In certain embodiments, the desired dosagecan be delivered using multiple administrations (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or more administrations). In other certain embodiments, the compound maybe administered via continuous intravenous (IV) infusion, such as usedby those commonly skilled in the art of general anesthesia.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. It will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually. Exemplarytherapeutically active agents include small organic molecules such asdrug compounds (e.g., compounds approved by the US Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins and cells.

The pharmaceutical composition may also be in combination with at leastone pharmacologically acceptable carrier. The carrier, also known in theart as an excipient, vehicle, auxiliary, adjuvant, or diluent, is anysubstance that is pharmaceutically inert, confers a suitable consistencyor form to the composition, and does not diminish the therapeuticefficacy of the compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic, or other untoward reaction when administered to a mammal orhuman, as appropriate.

The pharmaceutical compositions containing the compounds or steroids ofthe present disclosure may be formulated in any conventional manner.Proper formulation is dependent upon the route of administration chosen.The compositions of the disclosure can be formulated for any route ofadministration, so long as the target tissue is available via thatroute. Suitable routes of administration include, but are not limitedto, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous,rectal, subcutaneous, intramuscular, intraorbital, intracapsular,intraspinal, intraperitoneal, or intrasternal), topical (nasal,transdermal, intraocular), intravesical, intrathecal, enteral,pulmonary, intralymphatic, intracavital, vaginal, transurethral,intradermal, aural, intramammary, buccal, orthotopic, intratracheal,intralesional, percutaneous, endoscopical, transmucosal, sublingual, andintestinal administration. In certain embodiments, the route ofadministration is oral. In certain embodiments, the route ofadministration is parenteral. In certain embodiments, the route ofadministration is intravenous.

Pharmaceutically acceptable carriers for use in the compositions of thepresent disclosure are well known to those of ordinary skill in the artand are selected based upon a number of factors, including for example:the particular compound used, and its concentration, stability andintended bioavailability; the disease, disorder or condition beingtreated with the composition; the subject, its age, size and generalcondition; and/or the route of administration. Suitable carriers may bereadily determined by one of ordinary skill in the art. (See, forexample, J. G. Nairn, in: Remington's Pharmaceutical Science (A.Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517.)

The compositions may be formulated as tablets, dispersible powders,pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions,suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, orany other dosage form that can be administered orally. Techniques andcompositions for making oral dosage forms useful in the presentdisclosure are described in the following exemplary references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and,Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the present disclosure designed for oraladministration comprise an effective amount of a compound of thedisclosure in a pharmaceutically acceptable carrier. Suitable carriersfor solid dosage forms include sugars, starches, and other conventionalsubstances including lactose, talc, sucrose, gelatin,carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate,calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, cornstarch, potato starch, sodium saccharin, magnesium carbonate,tragacanth, microcrystalline cellulose, colloidal silicon dioxide,croscarmellose sodium, talc, magnesium stearate, and stearic acid.Further, such solid dosage forms may be uncoated or may be coated byknown techniques (e.g., to delay disintegration and absorption).

The compounds and steroids of the present disclosure may also beformulated for parenteral administration (e.g., formulated for injectionvia intravenous, intraarterial, subcutaneous, rectal, subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes). The compositions of thepresent disclosure for parenteral administration comprise an effectiveamount of the compound in a pharmaceutically acceptable carrier. Dosageforms suitable for parenteral administration include solutions,suspensions, dispersions, emulsions or any other dosage form that can beadministered parenterally. Techniques and compositions for makingparenteral dosage forms are known in the art. Typically formulations forparenteral administration are sterile or are sterilized beforeadministration.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide, 2-pyrrolidinone,1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g.,1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such asmonoacetin, diacetin, and triacetin, aliphatic or aromatic esters suchas ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzylacetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di,or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate,ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters ofsorbitan, fatty acid derived PEG esters, glyceryl monostearate,glyceride esters such as mono, di, or tri-glycerides, fatty acid esterssuch as isopropyl myristrate, fatty acid derived PEG esters such asPEG-hydroxyoleate and PEG-hydroxystearate, N-methylpyrrolidinone,pluronic 60, polyoxyethylene sorbitol oleic polyesters such aspoly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀monooleate, poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono-ricinoleate, polyoxyethylene sorbitan esters(such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80from ICI Americas, Wilmington, Del.), polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters (such as polyoxyl 40 hydrogenated castor oil,cyclodextrins or modified cyclodextrins (e.g.,beta-hydroxypropyl-cyclodextrin)), saccharide fatty acid esters (i.e.,the condensation product of a monosaccharide (e.g., pentoses, such asribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses suchas glucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fattyacid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfone, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzine; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

Other pharmaceutically acceptable solvents for use in the disclosure arewell known to those of ordinary skill in the art, and are identified inThe Handbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa.,1995), The United States Pharmacopeia 24, The National Formulary 19,(National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al.,and Use of Nonaqueous Solvents in Parenteral Products, J. of Pharm.Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

Preferred solvents include cyclodextrins or modified cyclodextrins(e.g., beta-hydroxypropyl-cyclodextrin) as well as oils rich intriglycerides, for example, safflower oil, soybean oil or mixturesthereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40hydrogenated castor oil. Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®.

Additional minor components can be included in the compositions of thedisclosure for a variety of purposes well known in the pharmaceuticalindustry. These components will for the most part impart propertieswhich enhance retention of the compound at the site of administration,protect the stability of the composition, control the pH, facilitateprocessing of the compound into pharmaceutical formulations, and thelike. Preferably, each of these components is individually present inless than about 15 wt % of the total composition, more preferably lessthan about 5 wt %, and most preferably less than about 0.5 wt % of thetotal composition. Some components, such as fillers or diluents, canconstitute up to 90 wt % of the total composition, as is well known inthe formulation art. Such additives include cryoprotective agents forpreventing reprecipitation, surface active, wetting or emulsifyingagents (e.g., lecithin, polysorbate-80, Tween® 80, Pluronic 60,polyoxyethylene stearate), preservatives (e.g.,ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol,phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben),agents for adjusting pH or buffering agents (e.g., acids, bases, sodiumacetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g.,glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetylalcohol, stearyl alcohol, guar gum, methyl cellulose,hydroxypropylcellulose, tristearin, cetyl wax esters, polyethyleneglycol), colorants, dyes, flow aids, non-volatile silicones (e.g.,cyclomethicone), clays (e.g., bentonites), adhesives, bulking agents,flavorings, sweeteners, adsorbents, fillers (e.g., sugars such aslactose, sucrose, mannitol, or sorbitol, cellulose, or calciumphosphate), diluents (e.g., water, saline, electrolyte solutions),binders (e.g., starches such as maize starch, wheat starch, rice starch,or potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropyl methylcellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents(e.g., starches such as maize starch, wheat starch, rice starch, potatostarch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone,agar, alginic acid or a salt thereof such as sodium alginate,croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc,stearic acid or salts thereof such as magnesium stearate, orpolyethylene glycol), coating agents (e.g., concentrated sugar solutionsincluding gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, or titanium dioxide), and antioxidants (e.g.,sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose,phenols, and thiophenols).

Dosage from administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

Those with ordinary skill in administering anesthetics can readilydetermine dosage and regimens for the administration of thepharmaceutical compositions of the disclosure or titrating to aneffective dosage for use in treating insomnia, mood disorders,convulsive disorders, anxiety or symptoms of ethanol withdrawal. It isunderstood that the dosage of the compounds will be dependent upon theage, sex, health, and weight of the recipient, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired. For any mode of administration, the actual amount of compounddelivered, as well as the dosing schedule necessary to achieve theadvantageous effects described herein, will also depend, in part, onsuch factors as the bioavailability of the compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present disclosureshould be sufficient to affect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the compound, whether administered orally or by another route, is anyamount that would result in a desired therapeutic response whenadministered by that route. The dosage may vary depending on the dosingschedule, which can be adjusted as necessary to achieve the desiredtherapeutic effect. The most preferred dosage will be tailored to theindividual subject, as is understood and determinable by one of ordinaryskill in the art without undue experimentation.

In one embodiment, solutions for oral administration are prepared bydissolving the compound in any pharmaceutically acceptable solventcapable of dissolving a compound (e.g., ethanol or methylene chloride)to form a solution. An appropriate volume of a carrier which is asolution, such as beta-hydroxypropyl-cyclodextrin, is added to thesolution while stirring to form a pharmaceutically acceptable solutionfor oral administration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration areprepared by dissolving a compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. The solvent can optionally be capable ofevaporating when the solution is dried under vacuum. An additionalcarrier can be added to the solution prior to drying, such asbeta-hydroxypropyl-cyclodextrin. The resulting solution is dried undervacuum to form a glass. The glass is then mixed with a binder to form apowder. The powder can be mixed with fillers or other conventionaltabletting agents and processed to form a tablet for oral administrationto a patient. The powder can also be added to any liquid carrier asdescribed above to form a solution, emulsion, suspension or the like fororal administration.

Emulsions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is an emulsion, suchas Liposyn® II or Liposyn® III emulsions, is added to the solution whilestirring to form a pharmaceutically acceptable emulsion for parenteraladministration to a patient.

Solutions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is a solution, suchas beta-hydroxypropyl-cyclodextrin, is added to the solution whilestirring to form a pharmaceutically acceptable solution for parenteraladministration to a patient.

If desired, the emulsions or solutions described above for oral orparenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable concentration prior to use as is known in the art.

Still further encompassed by the disclosure are kits (e.g.,pharmaceutical packs). The kits provided may comprise a compound asdescribed herein and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical carrier for dilution or suspensionof the pharmaceutical composition or compound. In some embodiments, thepharmaceutical composition or compound provided in the container and thesecond container are combined to form one unit dosage form.

Optionally, instructions for use are additionally provided in such kitsof the disclosure. Such instructions may provide, generally, forexample, instructions for dosage and administration. In otherembodiments, instructions may further provide additional detail relatingto specialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination with anadditional therapeutic agent.

4. Definitions

The term “steroid” as used herein describes an organic compoundcontaining in its chemical nucleus the cyclopenta[a]phenanthrene ringsystem.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this disclosure include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As used herein, a “subject” to which administration is contemplatedincludes, but is not limited to, mammals, e.g., humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)), other primates (e.g., cynomolgus monkeys, rhesusmonkeys) and commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs. In any aspect and/or embodiment of thedisclosure, the subject is a human.

As used herein, a “therapeutically effective amount” “an amountsufficient” or “sufficient amount” of a compound means the level, amountor concentration of the compound required for a desired biologicalresponse, e.g., analgesia.

The term “saturated” as used herein describes the state in which allavailable valence bonds of an atom (especially carbon) are attached toother atoms.

The term “unsaturated” as used herein describes the state in which notall available valence bonds along the alkyl chain are satisfied; in suchcompounds the extra bonds usually form double or triple bonds (chieflywith carbon).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₄ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₁₋₃, C₁₋₂, C₂₋₄, C₂₋₃ and C₃₋₄ alkyl, while“C₁₋₂₂ alkyl” is intended to encompass, for example, C₁, C₂, C₃, C₄,etc., as well as C₁₋₂₁, C₁₋₂₀, C₁₋₁₅, C₁₋₁₀, C₂₋₂₀, C₂₋₁₅, C₂₋₁₀, C₃₋₁₅,C₃₋₁₀, etc. alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group having from, in some embodiments, 1to 4 carbon atoms (“C₁₋₄ alkyl”), and in other embodiments 1 to 22carbon atoms (“C₁₋₂₂ alkyl”). In some embodiments, an alkyl group has 1to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl grouphas 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkylgroup has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkylgroup has 2 to 4 carbon atom (“C₂₋₄ alkyl”). In yet other embodiments,an alkyl group has 1 to 21 carbon atoms (“C₁₋₂₁ alkyl”), 1 to 20 carbonatoms (“C₁₋₂₀ alkyl”), 1 to 15 carbon atoms (“C₁₋₁₅ alkyl”), 1 to 10carbon atoms (“C₁₋₁₀ alkyl”), etc. Examples of such alkyl groups includemethyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), pentyl (C₅), and thelike.

As used herein, “alkenyl” or “alkene” refers to a radical of astraight-chain or branched hydrocarbon group having from, in someembodiments, 2 to 4 carbon atoms (“C₂₋₄ alkenyl”), and in otherembodiments 2 to 22 carbon atoms (“C₂₋₂₂ alkenyl”), and one or morecarbon-carbon double bonds. In some embodiments, an alkenyl group has 2to 3 carbon atoms (“C₂₋₃ alkenyl”). In some embodiments, an alkenylgroup has 2 carbon atoms (“C₂ alkenyl”). In yet other embodiments, analkenyl group has 2 to 21 carbon atoms (“C₂₋₂₁ alkenyl”), 2 to 20 carbonatoms (“C₂₋₂₀ alkenyl”), 2 to 15 carbon atoms (“C₂₋₁₅ alkenyl”), 2 to 10carbon atoms (“C₂₋₁₀ alkyl”), etc. The one or more carbon-carbon doublebonds can be internal (such as in 2-butenyl) or terminal (such as in1-butenyl). Examples of such alkenyl groups include ethenyl (C₂),1-propenyl (C3), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄),butadienyl (C₄), 1-pentenyl (C₅), 2-pentenyl (C₅), and the like.

As used herein, “alkynyl” or “alkyne” refers to a radical of astraight-chain or branched hydrocarbon group having from 2 to 4 carbonatoms and one or more carbon-carbon triple bonds (“C₂₋₁₀ alkynyl”). Insome embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₋₄ aryl”; e.g., anthracyl).

As used herein, “alkoxy” refers to an alkyl, alkenyl, or alkynyl group,as defined herein, attached to an oxygen radical.

Alkyl, alkenyl, alkynyl, and aryl groups, as defined herein, aresubstituted or unsubstituted, also referred to herein as “optionallysubstituted”. In general, the term “substituted”, whether preceded bythe term “optionally” or not, means that at least one hydrogen presenton a group (e.g., a carbon or nitrogen atom) is replaced with apermissible substituent, e.g., a substituent which upon substitutionresults in a stable compound, e.g., a compound which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that result in theformation of a stable compound. The present disclosure contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this disclosure, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary substituents include groups that contain a heteroatom (such asnitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogenatom), halogen (e.g., chlorine, bromine, fluorine, or iodine), aheterocycle, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol,ketals, acetals, esters and ethers.

EXAMPLES

The following Examples describe or illustrate various embodiments of thepresent disclosure. Other embodiments within the scope of the appendedclaims will be apparent to a skilled artisan considering thespecification or practice of the disclosure as described herein. It isintended that the specification, together with the Examples, beconsidered exemplary only, with the scope and spirit of the disclosurebeing indicated by the claims, which follow the Example.

Compound Chemistry

In accordance with the following methods and Examples, the followingcompounds were prepared using methods known in the industry.

In accordance with Scheme 1, the following compounds were prepared,using methods generally known in the art and as outlined below.

(2β,3α,5α)-3-Hydroxy-2-methoxy-androstan-17-one (1)

Compound 1 was prepared as described previously (see, e.g., Qian, etal., “Neurosteroid Analogues, 18. Structure-Activity Studies ofent-Steroid Potentiators of γ-Aminobutyric Acid Type A Receptors andComparison of Their Activities with Those of Alphaxalone andAllopregnanolone,” J. of Med. Chem., Vol. 57(1), pages 171-190 (2014)).

(2β,3α,5α)-2-Methoxy-17-methylene-androstan-3-ol (2)

To a stirred suspension of methyltriphenylphosphonium bromide (7.12 g,20 mmol) in THF (45 mL) was added solid potassium t-butoxide (2.0 g, 18mmol) and the mixture was heated at reflux for 1 h under a nitrogenatmosphere. A THF solution (10 mL) of compound 1 (650 mg, 2.1 mmol) wasadded to the resulting refluxing yellow, methylene triphenylphosphoranesolution using a syringe. Reflux was continued for 3 h. The reactionmixture was cooled to room temperature, water was added and the productwas extracted into EtOAc. The combined extracts were dried andconcentrated to give an oil. The crude product was purified by flashcolumn chromatography (silica gel eluted 20-40% EtOAc in hexanes) togive compound 2 as a white solid (580 mg, 90%): mp 131-133° C.; IRv_(max) 3369, 2930, 2851, 1654, 1451, 1371, 1256, 1214 cm⁻¹; ¹H NMR(CDCl₃) δ 4.60 (m, 2H), 3.93 (s, 1H), 3.34 (s, 1H), 3.33 (s, 3H), 2.45(m, 1H), 2.17 (m, 1H), 0.94 (s, 3H), 0.76 (s, 3H); ¹³C NMR (CDCl₃) δ161.9, 100.5, 80.7, 68.2, 56.6, 55.2, 54.4, 44.1, 39.0, 36.0, 35.7,35.5, 34.8, 32.1, 31.8, 29.3, 28.0, 24.0, 20.7, 18.5, 13.1.

(2β,3α,5α)-2-Methoxy-3-(methoxymethoxy)-17-methylene-androstane (3)

A mixture of compound 2 (620 mg, 1.94 mmol), Hunig's base (1.75 mL, 10mmol), chloromethyl methyl ether (0.45 mL, 6 mmol) dissolved in CH₂Cl₂(7 mL) was stirred at room temperature for 12 h. Aqueous NaHCO₃ (5%, 8mL) was added and the product extracted into CH₂Cl₂. The CH₂Cl₂ extractwas dried and concentrated to give an oil. The crude product waspurified by flash column chromatography (silica gel eluted with 15%EtOAc in hexanes) to give compound 3 as a colorless oil (650 mg, 92%):IR v_(max) 2930, 1655, 1451, 1371, 1218 cm⁻¹; ¹H NMR (CDCl₃) δ 4.64(apparent q, 2H, J=7 Hz), 4.57 (m, 2H), 3.75 (s, 1H), 3.38 (s, 1H), 3.35(s, 3H), 3.30 (s, 3H), 2.46 (m, 1H), 2.20 (m, 1H), 0.93 (s, 3H), 0.75(s, 3H); ¹³C NMR (CDCl₃) δ 161.9, 100.5, 95.2, 79.0, 73.4, 56.5, 55.2,55.1, 54.4, 44.1, 39.6, 36.1, 35.8, 35.7, 34.8, 31.8, 29.7, 28.1, 24.0,20.7, 18.5, 13.0.

(2β,3α,5α,17β)-2-Methoxy-3-(methoxymethoxy)-androstane-17-methanol (4)

To a solution of compound 3 (363 mg, 1 mmol) in THF (5 mL) was added9-BBN (6 mL, 0.5 M solution) in THF and the mixture was stirred at roomtemperature for 15 h. The reaction mixture was cooled to ° C. A mixtureof 30% hydrogen peroxide (15 mL) and 3 M aqueous NaOH (15 mL) was addedto the cold solution and stirred at room temperature for 2 h. Water (100mL) was added and the product was extracted into Et₂O. The Et₂O extractwas washed with brine, dried and concentrated to give a viscous liquid.The crude product was purified by flash column chromatography (silicagel eluted with 20-35% EtOAc in hexanes) to give compound 4 as an oil(323 mg, 85%): IR v_(max) 3401, 2929, 1448, 1381, 1219 cm⁻¹; ¹H NMR(CDCl₃) δ 4.60 (apparent q, 2H, J=7.0 Hz), 3.76 (m, 1H), 3.70 (s, 1H),3.61 (m, 1H), 3.43 (m, 1H), 3.30 (s, 3H), 3.25 (s, 3H), 0.87 (s, 3H),0.56 (s, 3H); ¹³C NMR (CDCl₃) δ 95.1, 78.8, 73.3, 64.1, 56.3, 55.8,55.1, 52.7, 41.7, 39.4, 38.6, 36.0, 35.6, 34.4, 31.9, 29.6, 28.0, 27.2,25.5, 24.3, 22.5, 20.4, 12.9, 12.4.

(2β,3α,5α,17β)-17-Hydroxymethyl-2-methoxy-3-(methoxymethoxy)-androstan-18-oicacid, γ-lactone (5)

To a solution of compound 4 (300 mg, 0.79 mmol) in cyclohexane (50 mL)maintained at reflux by irradiation with a high intensity tungsten lampwere added iodine (345 mg, 2.7 mmol) and lead tetraacetate (1.35 g, 3mmol)) and the mixture was allowed to reflux for 80 min. One moreportion of lead tetraacetate (0.75 g, 1.7 mmol) was added and reflux wascontinued for another 50 minutes. The hot cyclohexane solution wasfiltered through a pad of celite and the filtrate was collected. Thefilter cake was washed with EtOAc and the washings were collected. Thecombined filtrate and washings were concentrated to give a brownsolution containing some particulate material. Solvents were removed andthe crude product was dissolved in acetone and stirred at roomtemperature. Jones reagent was added dropwise until an orange colorpersisted. The excess Jones reagent was consumed by adding few drops of2-propanol and the solution was diluted with water and the productextracted into EtOAc. The extract was washed with brine, dried andconcentrated to give a colorless oil which was purified by flash columnchromatography (silica gel eluted with 15-25% EtOAc in hexanes) to giveto give compound 5 an oil (150 mg, 48%). IR v_(max) 2931, 1760, 1447,1370, 1236 cm⁻¹; ¹H NMR (CDCl₃) δ 4.66 (apparent q, 2H, J=6.7 Hz), 4.30(dd, 1H, J=9.0 Hz, J=5.1 Hz) 4.06 (d, 1H, J=9.0 Hz), 3.76 (s, 1H), 3.39(s, 1H), 3.36 (s, 3H), 3.30 (s, 3H), 0.99 (s, 3H), 0.93 (m, 1H) 0.75 (m,1H); ¹³C NMR (CDCl₃) δ 179.5, 95.3, 78.9, 73.5, 72.2, 56.5, 55.33,55.28, 54.2, 53.4, 45.2, 39.6, 36.2, 35.8, 32.9, 32.3, 31.7, 31.4, 29.7,27.9, 27.3, 20.2, 13.1.

1-[(2β,3α,5α,17β)-17-Hydroxymethyl-2-methoxy-3-(methoxymethoxy)-18-norandrostan-13-yl]ethanone(6)

To a refluxing solution of compound 5 (115 mg, 0.29 mmol) in Et₂O wasadded CH₃Li (2 M in Et₂O, 2 mL, 4 mmol) and the mixture was heated atreflux for 40 minutes. The reaction mixture was cooled to 0° C. andwater (20 mL) was added. The biphasic solution was separated the aqueouslayer extracted with Et₂O. The combined original Et₂O layer and Et₂Oextracts were washed with brine dried and concentrated to give acolorless oil which was purified by flash column chromatography onsilica gel to give compound 6 as an oil (90 mg, 78%): IR v_(max) 3468,2928, 1694, 1448, 1356 cm⁻¹; ¹H NMR (CDCl₃) δ 4.65 (apparent q, 2H,J=6.6 Hz), 3.75 (s, 1H), 3.50 (m, 2H), 3.36 (s, 3H), 3.35 (s, 1H), 3.30(s, 3H), 2.68 (m, 1H), 2.20 (s, 3H), 0.82 (s, 3H), 0.77 (m, 1H); ¹³C NMR(CDCl₃) δ 213.9, 95.3, 78.9, 73.5, 63.9, 61.1, 57.6, 56.5, 55.3, 53.0,39.6, 36.3, 36.1, 35.7, 35.7, 31.9, 30.3, 29.7, 27.9, 25.7, 24.8, 23.1,13.2.

(2β,3α,5α,17β)-13-Acetyl-2-methoxy-3-(methoxymethoxy)-18-norandrostan-17-carboxaldehyde(7)

Compound 6 (65 mg, 0.16 mmol) was stirred in a DMSO (4 mL) solution ofiodoxybenzoic acid (622 mg, 45% by weight, 1 mmol) at room temperaturefor 3 h. Water was added and the product extracted into EtOAc. Theextract was washed with brine, dried and concentrated to give an oilwhich was purified by filtering through a short silica gel column elutedwith 30% ethyl acetate hexanes to yield compound 7 which was dissolvedin THF and kept at 0° C. and immediately converted withoutcharacterization (¹H NMR confirmed the presence of the aldehyde group)to compound 8.

1-[(2α,3α,5α)-2-Methoxy-3-(methoxymethoxy)-18-norpregn-20-en-13-yl]ethanone(8)

To a stirred suspension of methyltriphenylphosphonium bromide (7.12 g,20 mmol) in THF (45 mL) was added solid potassium t-butoxide (2.0 g, 18mmol) and the mixture was heated at reflux for 1 h under a nitrogenatmosphere. The reaction was cooled to room temperature and compound 7in THF was added in portions until monitoring by TLC analysis showedcompound 7 was converted into a product. Water was added and the productextracted into EtOAc. The extract was dried and concentrated to give anoil which was purified by flash column chromatography (silica gel elutedwith 15-35% EtOAc in hexanes) to give product 8 as a viscous oil (40 mg,62%): IR v_(max) 2928, 1698, 1448 cm⁻¹; ¹H NMR (CDCl₃) δ 5.60 (m, 1H),5.05 (m, 2H), 4.66 (apparent q, 2H, J=7.1 Hz), 3.77 (s, 1H), 3.38 (s,3H), 3.35 (s, 1H), 3.30 (s, 3H), 2.45 (m, 1H), 2.25 (m, 1H), 2.05 (s,3H), 0.83 (s, 3H), 0.77 (m, 1H); ¹³C NMR (CDCl₃) δ 212.7, 138.7, 115.6,95.3, 79.0, 73.5, 63.0, 57.2, 56.6, 55.5, 55.4, 55.1, 39.7, 36.3, 35.7,35.6, 34.8, 32.0, 30.4, 29.7, 28.2, 28.0, 25.1, 23.0, 13.2.

1-[(2β,3α,5α)-3-Hydroxy-2-Methoxy-18-norpregn-20-en-13-yl]ethanone (9,KK-140)

Compound 8 (55 mg, 0.14 mmol) in THF (5 mL) and 6 N HCl (2 mL) wasstirred at room temperature for 8 h. The solution was made basic withaqueous NaHCO₃ and the product extracted into CH₂Cl₂. The extract waswashed with brine, dried and concentrated to give an oil. The oil washeated at 150° C. under vacuum for 1 h to remove traces of4-chlorobutanol and the crude product was purified by flash columnchromatography (silica gel eluted with 20-40% EtOAc in hexanes) to givecompound 9 as a white solid (38 mg, 78%): mp 155-157° C.; [α]_(D) ²³−6.0 (c 0.05, CHCl₃); IR v_(max) 3369, 2930, 2859, 1694, 1445, 1356,1242 cm⁻¹; ¹H NMR (CDCl₃) δ 5.62 (m, 1H), 5.05 (m, 2H), 3.94 (b s, 1H),3.32 (b s, 1H), 3.31 (s, 3H), 2.46 (m, 1H), 2.26 (m, 1H), 2.05 (s, 3H),0.82 (s, 3H); ¹³C NMR (CDCl₃) δ 212.7, 138.6, 115.6, 80.6, 68.2, 63.0,57.2, 56.7, 55.5, 55.0, 39.1, 36.0, 35.6, 35.6, 34.7, 32.1, 32.0, 30.3,28.2, 27.9, 25.1, 23.0, 13.2. Anal. (C₂₃H₃₆O₃): C, 76.62%; H, 10.06%.Found: C, 76.66%; H, 10.02%.

In accordance with Scheme 2, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3β)-3-(Methoxymethoxy)-androst-5-en-17-one (10)

Previously reported compound 10 (6.64 g) was prepared by the proceduredescribed for the preparation of compound 3 from compound 2 (see Kaji,et al., “Synthesis of 3-epi-6,7-dideoxyxestobergsterol A,” Chem. &Pharm. Bulletin, Vol. 48(10), pages 1480-1483 (2000)).

(3β)-3-(Methoxymethoxy)-17-methylene-androstane (11)

To a stirred suspension of methyltriphenylphosphonium bromide (21.40 g,60 mmol) in THF (160 mL) was added solid potassium t-butoxide (6.5 g, 58mmol) and the mixture was heated at reflux for an hour under nitrogenatmosphere. A THF solution (60 mL) of compound 10 (6.64 g, 20 mmol) wasadded using a syringe and refluxing was continued for 3 h. After coolingto room temperature, water was added and the product extracted intoEtOAc. The extract was dried and concentrated to give an oil which waspurified by flash column chromatography (silica gel eluted with 2-20%EtOAc in hexanes) to give compound 11 as a white solid (6.08 g, 91%): mp76-78° C.; IR v_(max) 3067, 2939, 2851, 1655, 1465, 1437, 1372, 1213cm⁻¹; ¹H NMR (CDCl₃) δ 5.37 (b s, 1H), 4.69 (s, 2H), 4.64 (b s, 2H),3.43 (m, 1H), 3.37 (s, 3H), 1.03 (s, 3H), 0.80 (s, 3H); ¹³C NMR (CDCl₃)δ 161.7, 140.8, 121.5, 100.9, 94.6, 76.8, 55.1, 54.7, 50.3, 43.8, 39.5,37.2, 36.8, 35.5, 31.74, 31.69, 29.4, 28.9, 24.2, 20.9, 19.4, 18.2.

(3β,17β)-3-(Methoxymethoxy)-androst-5-ene-17-methanol (12)

To a solution of compound 11 (6 g, 18 mmol) in THF (40 mL) was added9-BBN (64 mL, 0.5 M solution in THF) in THF and reaction was stirred atroom temperature for 15 h. After cooling to 0° C., 30% hydrogen peroxide(50 mL) and 3 M aqueous NaOH (50 mL) were added and stirring wascontinued at room temperature for 2 h. Water (250 mL) was added and theproduct was extracted into Et₂O. The extract was washed with brine,dried and concentrated to give a viscous liquid which was purified bycolumn chromatography (silica gel eluted with 20-35% EtOAc in hexanes togive compound 12 as a white solid (5.26 g, 84%): mp 102-105° C.; IRv_(max) 3325, 1448, 1379 cm⁻¹; ¹H NMR (CDCl₃) δ 5.35 (b s, 1H), 4.68 (s,2H), 3.71 (dd, 1H, J=10.5 Hz, J=7.0 Hz), 3.53 (dd, 1H, J=10.5 Hz, J=7.5Hz), 3.42 (m, 1H), 3.36 (s, 3H), 1.01 (s, 3H), 0.65 (s, 3H); ¹³C NMR(CDCl₃) δ 140.7, 121.6, 94.6, 76.9, 64.5, 56.2, 55.1, 52.9, 50.3, 41.6,39.5, 38.5, 37.2, 36.7, 31.9, 31.5, 28.8, 25.5, 24.6, 20.7, 19.3, 12.6.

(3β,17β)-17-(Benzyloxymethyl)-3-methoxymethoxy-androst-5-ene (13)

NaH (5.7 g, 143 mmol, 60% suspension in mineral oil), compound 12 (5 g,14.3 mmol) and benzyl bromide (5 mL, 43 mmol) in THF (150 mL) was heatedat reflux for 12 h. After cooling to 0° C., excess sodium hydride wasquenched by careful addition of MeOH. Water (200 mL) was added and theproduct extracted into EtOAc. The extract was dried and concentrated togive an oil. The excess benzyl bromide was removed at 150° C. under highvacuum and the product was purified by flash column chromatography(silica gel eluted with hexanes followed by 10-20% EtOAc in hexanes) togive compound 13 as a white solid (5.7 g, 91%): mp 75-76° C.; IR v_(max)2937, 1453, 1366, 1212 cm⁻¹; ¹H NMR (CDCl₃) δ 7.28-2.20 (m, 5H), 5.21 (bs, 1H), 4.63 (s, 2H), 4.43 (apparent q, 2H, J=11.1 Hz), 4.47 (dd, 1H,J=10.5 Hz, J=7.0 Hz), 3.37 (m, 1H), 3.31 (s, 3H), 3.30 (m, 1H), 0.96 (s,3H), 0.56 (s, 3H); ¹³C NMR (CDCl₃) δ 140.7, 138.8, 128.3 (2×C), 127.4(2×C), 127.3, 121.6, 94.7, 76.9, 73.0, 72.1, 56.1, 55.2, 50.4, 49.9,41.7, 39.5, 38.4, 37.2, 36.8, 32.0, 31.6, 28.9, 25.9, 24.7, 20.8, 19.4,12.3.

(3β,5α,17β)-17-(Benzyloxymethyl)-3-(methoxymethoxy)-androstan-6-one (14)

To a solution of compound 13 (5.6 g, 12.8 mmol) in THF (45 mL) was addedBH₃.THF (26 mL, 1 M solution in THF) the reaction was stirred at 0° C.for 3 h. Then 30% hydrogen peroxide (35 mL) and 5 M aqueous NaOH (35 mL)was carefully added at 0° C. and stirring was continued at roomtemperature for 3 h. Water (200 mL) was added and the extracted intoEtOAc. The extract was washed with brine, dried and concentrated to givea viscous liquid. The crude product was purified by flash columnchromatography (silica gel eluted with 20-35% EtOAc in hexanes) to givea mixture of the 5α-reduced 6α-alcohol and the 5β-reduced 6β-alcohol(4.7 g, 80%) which was oxidized immediately without any furthercharacterization.

To a solution of the hydroboration products (4.7 g, 10.3 mmol) in CH₂Cl₂(100 mL) was added pyridinium chlorochromate (4.44 g, 20.6 mmol) and thereaction was stirred at room temperature for 4 h. Hexane (30 mL) wasadded and the supernatant liquid was transferred to a silica gel columnand eluted with 20% EtOAc in hexanes to give mixture of the6α/6β-ketones as a white solid. The ketone mixture and potassiumcarbonate (2 g) in MeOH (20 mL) was heated at reflux for 3 h, thencooled to room temperature and diluted with water (100 mL). The productwas extracted first with Et₂O and then with EtOAc. The combined organiclayers were washed with brine, dried and concentrated to give acolorless viscous liquid which was purified by column chromatography(silica gel eluted with 25% EtOAc in hexanes) to give compound 14 as acolorless liquid (4.2 g, 90%): IR v_(max) 2944, 1711, 1469, 1453, 1366,1254, 1209 cm⁻¹; ¹H NMR (CDCl₃) δ 7.36-7.20 (m, 5H), 4.70 (apparent q,2H, J=9.8 Hz), 4.53 (apparent q, 2H, J=12.1 Hz), 3.53 (m, 2H), 3.79 (s,3H), 3.78 (m, 1H), 2.32 (dd, 1H, J=12.9 Hz, J=4.3 Hz), 2.20 (dd, 1H,J=12.2 Hz, J=2.4 Hz), 0.78 (s, 3H), 0.63 (s, 3H); ¹³C NMR (CDCl₃) δ210.7, 138.6, 128.2, 127.4, 127.3, 94.3, 75.1, 73.0, 71.9, 56.7, 56.1,55.1, 54.1, 49.8, 46.7, 42.3, 41.1, 38.1, 37.6, 36.7, 28.1, 26.9, 25.5,24.3, 21.2, 13.1, 12.4.

(3β,5α,6β,17β)-17-(Benzyloxymethyl)-3-(methoxymethoxy)-androstan-6-ol(15)

To a cold solution (0° C.) of compound 14 (3.2 g, 7 mmol) in THF (15 mL)was added LiAlH₄ (2 M in THF, 7 mL) and the reaction was stirred at roomtemperature for 2 h. Then Et₂O (100 mL) was added and water (1.5 mLadded dropwise) and stirring was continued for 15 min. Aqueous 5 M NaOH(1.5 mL) was then added and after stirring for another 15 min, aqueous 5M NaOH (2 mL) was again added and stirring continued for another 30 min.The supernatant was removed and dried and concentrated to give an oilwhich was purified by flash column chromatography (silica gel elutedwith 20-40% EtOAc in hexanes) to give compound 15 (2.9 g, 90%) as anoil: IR v_(max) 3479, 2934, 1453, 1365, 1209 cm⁻¹; ¹H NMR (CDCl₃) δ7.36-7.20 (m, 5H), 4.68 (apparent q, 2H, J=7.1 Hz), 4.68 (apparent q,2H, J=12.1 Hz), 3.78 (b s, 1H), 3.51 (m, 2H), 3.36 (s, 3H), 3.35 (m,1H), 1.02 (s, 3H), 0.62 (s, 3H); ¹³C NMR (CDCl₃) δ 138.8, 128.2, 127.4,127.3, 94.5, 76.6, 73.0, 72.2, 71.9, 55.6, 55.1, 54.5, 50.1, 47.4, 42.0,39.6, 38.5, 35.6, 32.4, 30.1, 28.7, 25.9, 24.6, 20.7, 15.7, 12.6.

(3β,5α,6β,17β)-17-(Benzyloxymethyl)-6-methoxy-3-(methoxymethoxy)-androstane(16)

NaH (5.7 g, 143 mmol, 60% suspension in mineral oil) and compound 15(2.51 g, 5.5 mmol) and methyl iodide (10 mL) in THF (100 mL) was heatedat 60° C. for 14 h. The reaction was cooled to 0° C. and the excess NaHwas quenched by careful addition of MeOH. Water (150 mL) was added andthe product extracted into EtOAc. The extract was dried and concentratedto give an oil which was purified by flash column chromatography (silicagel eluted with hexanes followed by 10-15% EtOAc in hexanes) to givecompound 16 as an oil (2.38 g, 92%): IR v_(max) 2932, 1454, 1366 cm⁻¹;¹H NMR (CDCl₃) δ 7.30-7.20 (m, 5H), 4.63 (apparent q, 2H, J=7.0 Hz),4.43 (s, 2H), 3.47 (m, 2H), 3.32 (s, 3H), 3.31 (m, 1H), 3.19 (s, 3H),3.12 (s, 1H), 0.90 (s, 3H), 0.57 (s, 3H); ¹³C NMR (CDCl₃) δ 138.9, 128.2(2×C), 127.4 (2×C), 127.3, 94.4, 81.3, 73.0, 72.2, 57.5, 55.6, 55.1,54.7, 50.1, 47.8, 42.1, 38.6, 38.4, 36.0, 34.7, 32.7, 30.5, 28.7, 26.0,24.7, 20.7, 15.4 (2×C), 12.6.

(3β,5α,6β,17β)-17-(Benzyloxymethyl)-6-methoxy-androstan-3-ol (17)

Compound 16 (2.3 g, 4.9 mmol) in MeOH (15 mL) and aqueous 6 N HCl (6 mL)was stirred at room temperature for 8 h. The reaction was made basicwith aqueous NaHCO₃ and the product extracted into CH₂Cl₂. The extractwas washed with brine, dried and concentrated to give an oil which waspurified by flash column chromatography (silica gel eluted with 30-40%EtOAc in hexanes) to give compound 17 as an oil (2.0 g, 100%). IRv_(max) 3369, 2931, 1454, 1366 cm⁻¹; ¹H NMR (CDCl₃) δ 7.30-7.20 (m, 5H),4.51 (apparent q, 2H, J=12.0 Hz), 3.55 (m, 2H), 3.36 (m, 1H), 3.27 (s,3H), 3.20 (s, 1H), 0.98 (s, 3H), 0.66 (s, 3H); ¹³C NMR (CDCl₃) δ 138.6,128.1 (2×C), 127.3 (2×C), 127.2, 81.2, 72.8, 72.0, 71.5, 57.3, 55.5,54.5, 49.9, 47.6, 41.9, 38.4, 38.3, 35.6, 35.5, 34.5, 32.3, 30.3, 25.8,24.5, 20.6, 15.3, 12.5.

(5α,6β,17β)-17-(Benzyloxymethyl)-6-methoxy-androstan-3-one (18)

Compound 17 (1.92 g, 4.5 mmol) was dissolved in acetone (20 mL) at 0° C.and Jones reagent was added until an orange color persisted. The excessJones reagent was consumed by adding few drops of 2-propanol. Water (100mL) was added and the product extracted into EtOAc. The extract waswashed with brine, dried and concentrated to give an oil which waspurified by flash column chromatography (silica gel eluted with 15-25%EtOAc in hexanes) to give compound 18 as a viscous liquid (1.82 g, 95%):IR v_(max) 2935, 1711, 1453 cm⁻¹; ¹H NMR δ (CDCl₃) 7.30-7.20 (m, 5H),4.51 (apparent q, 2H, J=12.1 Hz), 3.56 (dd, 1H, J=9.4 Hz, J=7.0 Hz),3.39 (dd, 1H, J=9.4 Hz, J=7.0 Hz), 3.26 (s, 3H), 3.15 (s, 1H), 2.87 (t,1H, J=14.4 Hz), 2.47-2.28 (m, 2H), 1.15 (s, 3H), 0.68 (s, 3H); ¹³C NMR δ213.3, 138.7, 128.2 (2×C), 127.39 (2×C), 127.3, 79.9, 73.0, 72.1, 57.3,55.4, 54.0, 50.0, 49.1, 42.1, 42.0, 39.6, 38.4, 38.1, 35.9, 34.0, 30.3,25.9, 24.6, 20.9, 14.6, 12.6.

(3α,5α,6β,17β)-17-(Benzyloxymethyl)-6-methoxy-androstan-3-ol (19)

To a cold solution (−78° C.) of compound 19 (1.7 g, 4 mmol) in THF wasadded 1M K-Selectride in THF (4.5 mmol) and the reaction was stirred at−78° C. for 2 h. A few drops acetone was added to consume the excessK-Selectride and the reaction was brought to 0° C. Then 30% hydrogenperoxide (15 mL) and 3 M aqueous NaOH (15 mL) were added to the coldsolution and stirring was continued at room temperature for 2 h. Water(100 mL) was added and the product was extracted into EtOAc. The extractwas washed with brine, dried and concentrated to give a viscous liquidwhich was purified by flash column chromatography (silica gel elutedwith 20-35% EtOAc in hexanes to give the desired alcohol as an oil (1.28g, 76%): IR v_(max) 3369, 2931, 1454, 1367, 1265 cm⁻¹; ¹H NMR (CDCl₃) δ7.35-7.25 (m, 5H), 4.50 (apparent q, 2H, J=12.0 Hz), 4.16 (s, 1H), 3.54(dd, 1H, J=9.0 Hz, J=6.7 Hz), 3.39 (dd, 1H, J=9.0 Hz, J=7.0 Hz), 3.24(s, 3H), 3.13 (s, 1H), 0.93 (s, 3H), 0.63 (s, 3H); ¹³C NMR (CDCl₃) δ138.7, 128.2 (2×C), 127.4 (2×C), 127.3, 81.4, 73.0, 72.2, 67.0, 57.2,55.6, 54.6, 50.0, 42.1, 42.0, 38.5, 36.4, 34.3, 33.7, 33.1, 30.4, 29.0,25.9, 24.6, 20.6, 20.3, 14.4, 12.6.

(3α,5α,6β,17β)-17-(Benzyloxymethyl)-6-methoxy-3-(methoxymethoxy)-androstane(20)

Compound 19 (1.2 g, 2.83 mmol), Hunig's base (1.75 mL, 10 mmol),chloromethyl methyl ether (0.45 mL, 6 mmol) in CH₂Cl₂ (8 mL) was stirredat room temperature for 12 h. Aqueous NaHCO₃ (5%, 10 mL) was added andthe product extracted into CH₂Cl₂. The extract was dried andconcentrated to give an oil which was purified by flash columnchromatography (silica gel eluted with 15% EtOAc in hexanes) to givecompound 20 as a colorless oil (1.29 g, 97%): IR v_(max) 2930, 1588,1454, 1366, 1200 cm⁻¹; ¹H NMR (CDCl₃) δ 7.35-7.25 (m, 5H), 4.70(apparent q, 2H, J=6.7 Hz), 4.53 (apparent q, 2H, J=12.0 Hz), 3.96 (s,1H), 3.56 (dd, 1H, J=9.0 Hz, J=7.1 Hz), 3.41 (s, 3H), 3.40 (m, 1H), 3.28(s, 3H), 3.18 (s, 1H), 0.99 (s, 3H), 0.68 (s, 3H); ¹³C NMR (CDCl₃) δ138.8, 128.2 (2×C), 127.3 (2×C), 127.2, 94.4, 81.4, 72.9, 72.2, 72.0,57.2, 55.6, 55.1, 54.6, 50.0, 42.8, 42.0, 38.5, 36.2, 34.4, 34.3, 31.1,30.4, 26.3, 25.9, 24.6, 20.2, 14.6, 12.6.

(3α,5α,6β,17β)-6-Methoxy-3-(methoxymethoxy)-androstane-17-methanol (21)

Compound 20 (941 mg, 2 mmol), 5% Pd—C in EtOAc was treated with H₂ (60psi) in a Parr hydrogenator for 14 h. The Pd—C was removed and theproduct purified by flash column chromatography (silica gel eluted with50% EtOAc in hexanes) to give compound 21 as a colorless liquid (730 mg,96%): IR v_(max) 3369, 2930, 1591, 1455 cm⁻¹; ¹H NMR (CDCl₃) δ 4.67(apparent q, 2H, J=7.0 Hz), 3.92 (t, 1H, J=2.7 Hz), 3.73 (m, 1H), 3.55(m, 1H), 3.37 (s, 3H), 3.24 (s, 3H), 3.14 (s, 1H), 0.95 (s, 3H), 0.67(s, 3H); ¹³C NMR (CDCl₃) δ 94.5, 81.5, 72.1, 64.7, 57.3, 55.8, 55.2,54.6, 53.1, 42.8, 42.0, 38.8, 36.3, 34.5, 34.3, 31.2, 30.3, 26.3, 25.5,24.6, 20.3, 14.7, 12.7.

(3α,5α,6β,17β)-17-Hydroxymethyl-6-methoxy-3-(methoxymethoxy)-androstan-18-oicacid, γ-lactone (22)

Compound 22 (210 mg, 48%) was prepared as an oil from compound 21 usingthe procedure described for the preparation of compound 5 from compound4. Compound 22 had: IR v_(max) 2933, 1757, 1591, 1455, 1369 cm⁻¹; ¹H NMR(CDCl₃) δ 4.65 (apparent q, 2H, J=6.7 Hz), 4.32 (dd, 1H, J=9.0 Hz, J=5.5Hz), 4.07 (d, 1H, J=9.4 Hz), 3.91 (t, 1H, J=2.8 Hz), 3.36 (s, 3H), 3.21(s, 3H), 3.13 (apparent q, 1H, J=2.8 Hz), 2.54 (m, 1H), 2.30 (m, 1H),1.00 (s, 3H); ¹³C NMR (CDCl₃) δ 179.3, 94.5, 80.9, 72.2, 72.1, 57.0,55.2, 55.1, 53.7, 53.4, 45.3, 42.8, 36.3, 34.6, 34.4, 31.7, 31.3, 31.1,29.1, 27.3, 26.3, 19.9, 14.6.

1-[(3α,5α,6β,17β)-17-Hydroxymethyl-6-methoxy-3-(methoxymethoxy)-18-norandrostan-13-yl]ethanone(23)

Compound 23 (110 mg, 50%) was prepared as an oil from compound 22 usingthe procedure described for the preparation of compound 6 from compound5. Compound 23 had: IR v_(max) 3446, 2931, 2874, 1696, 1593, 1462, 1368cm⁻¹; ¹H NMR (CDCl₃) δ 4.65 (apparent q, J=6.6 Hz), 3.91 (t, 1H, J=2.7Hz), 3.60 (m, 2H), 3.37 (s, 3H), 3.23 (s, 3H), 3.13 (br s, 1H), 2.70 (td, 1H, J=12.7 Hz, J=3.2 Hz), 2.22 (s, 3H), 0.83 (s, 3H); ¹³C NMR (CDCl₃)δ 213.7, 94.5, 81.0, 64.0, 61.0, 57.4, 57.0, 55.1, 54.9, 53.1, 42.8,36.3, 36.2, 34.4, 33.9, 31.5, 31.1, 30.4, 26.2, 26.0, 25.0, 22.9, 14.7.

(3α,5α,6β,17β)-13-Acetyl-6-methoxy-3-(methoxymethoxy)-8-norandrostan-17-carboxaldehyde(24)

Compound 24 was prepared from compound 23 using the procedure describedfor the preparation of compound 7 from compound 6. Compound 24 wasimmediately converted without characterization (¹H NMR confirmed thepresence of the aldehyde group) to compound 25.

1-[(3α,5α,6δ)-6-Methoxy-3-(methoxymethoxy)-18-norpregn-20-en-13-yl]ethanone(25)

Compound 25 (80 mg, 78%) was obtained as an oil from compound 24 usingthe procedure described for the preparation of compound 8 from compound7. Compound 25 had: IR v_(max) 2931, 1699, 1462, 1358, 1195, 1450 cm⁻¹;¹H NMR (CDCl₃) δ 5.63 (m, 1H), 5.07 (m, 2H), 4.66 (apparent q, J=6.7Hz), 3.91 (b s, 1H), 3.23 (s, 3H), 3.23 (s, 3H), 3.13 (b s, 1H), 2.45(m, 1H), 2.28 (m, 1H), 2.10 (m, 1H), 2.06 (s, 3H), 0.84 (s, 3H); ¹³C NMR(CDCl₃) δ 212.4, 138.6, 115.7, 94.5, 81.0, 72.0, 62.9, 57.0, 56.9,55.14, 55.07, 55.0, 42.8, 36.2, 34.7, 34.5, 33.9, 31.5, 31.1, 30.4,28.2, 26.3, 25.2, 22.7, 14.7.

1-[(3α,5α,6β)-3-Hydroxy-6-methoxy-18-norpregn-20-en-13-yl]ethanone (26,KK-143)

Compound 26 (33 mg, 77%) was prepared from compound 25 as a white solidusing the procedure described for the preparation of compound 9 fromcompound 8. Compound 26 had: mp 158-160° C.; [α]_(D) ²³ −49 (c 0.065,CHCl₃); IR v_(max) 3308, 2936, 2867, 1698, 1430 cm⁻¹; ¹H NMR (CDCl₃) δ5.62 (m, 1H), 5.06 (m, 2H), 4.13 (t, 1H, J=2.8 Hz), 3.22 (s, 3H), 3.12(b s, 1H), 2.44 (m, 1H), 2.29 (m, 1H), 2.10 (m, 1H), 2.05 (s, 3H), 0.81(s, 3H); ¹³C NMR (CDCl₃) δ 212.4, 138.6, 115.7, 80.9, 66.8, 62.9, 57.0,56.9, 55.1, 42.1, 36.4, 34.7, 33.9, 33.8, 33.2, 31.4, 30.3, 29.0, 28.1,25.2, 22.7, 14.5. HRMS (FAB) Calcd for C₂₃H₃₆O₃Na: 283.2562. Found:283.2565.

In accordance with Scheme 3, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3α,5α)-3-(Methoxymethoxy)-androstane-11,17-dione (27)

Compound 27 was prepared as described previously (see Bandyopadhyaya, etal., “Neurosteroid analogues. 15. A comparative study of the anestheticand GABAergic actions of alphaxalone, Δ16-alphaxalone and theircorresponding 17-carbonitrile analogues,” Bioorganic & MedicinalChemistry Letters, Vol. 20(22), pages 6680-6684 (2010)).

(3α,5α)-3-(Methoxymethoxy)-17-methylene-androstan-11-one (28)

Compound 28 (810 mg, 78%) was prepared from compound 27 as a low meltingsolid using the procedure described for the preparation of compound 11from compound 10. Compound 28 had: IR v_(max) 2924, 1702, 1656, 1454,1374 cm⁻¹; ¹H NMR (CDCl₃) δ 4.63 (m, 4H), 3.81 (b s, 1H), 3.35 (s, 3H),2.6-2.19 (m, 4H), 1.02 (s, 3H), 0.72 (s, 3H); ¹³C NMR (CDCl₃) δ 210.8,158.7, 102.1, 94.4, 71.3, 64.7, 55.1, 54.2, 53.8, 47.9, 39.6, 36.6,35.5, 33.2, 32.3, 31.5, 29.6, 27.9, 25.9, 23.8, 19.3, 11.1.

(3α,5α,11β)-3-(Methoxymethoxy)-17-methylene-androstan-11-ol (29)

To a cold solution (0° C.) of compound 28 (693 mg, 2 mmol) in Et₂O (15mL) was added LiAlH₄ (2 M in THF, 4 mL) and the reaction was stirred atroom temperature for 2 h. Then Et₂O (50 mL) and water (0.5 mL) wereadded and stirring was continued for 15 min. Aqueous 5 M NaOH (0.5 mL)was then added and after stirring for 15 min, additional 5 M aqueousNaOH (1 mL) was added and stirring continued for another 30 min. Thesupernatant was removed and concentrated to give an oil which waspurified by flash column chromatography (silica gel eluted with 15-40%EtOAc in hexanes) to give compound 29 (570 mg, 82%) as an oil: IRv_(max) 3501, 3066, 2923, 1654, 1445 cm⁻¹; ¹H NMR (CDCl₃) δ 4.60 (m,4H), 4.35 (b s, 1H), 3.81 (b s, 1H), 3.34 (s, 3H), 2.45 (m, 1H), 2.20(m, 1H), 1.93 (dd, 1H, J=14.1 Hz, J=2.0 Hz), 1.02 (s, 3H), 0.97 (s, 3H),0.81 (dd, 1H, J=10.9 Hz, J=2.7 Hz); ¹³C NMR (CDCl₃) δ 161.6, 100.3,94.3, 71.2, 67.9, 58.3, 55.9, 55.0, 44.5, 43.1, 40.5, 36.0, 32.9, 32.4,32.0, 31.1, 28.9, 27.9, 25.9, 23.9, 20.7, 14.4.

(3α,5α,11β)-11-Methoxy-3-(methoxymethoxy)-17-methylene-androstane (30)

NaH (1.6 g, 40 mmol, 60% suspension in mineral oil) and compound 29 (560mg, 1.6 mmol) in THF (35 mL) and methyl iodide (6 mL) was heated at 60°C. for 14 h. The reaction mixture was cooled to 0° C. and the excess NaHconsumed by careful addition of MeOH. Water (80 mL) was added and theproduct extracted into EtOAc. The extract was dried and concentrated togive an oil which was purified by flash column chromatography (silicagel eluted with hexanes followed by 10-15% EtOAc in hexanes) to givecompound 30 as an oil (469 mg, 81%). IR v_(max) 3067, 2920, 1655, 1456,1369 cm⁻¹; ¹H NMR (CDCl₃) δ 4.65 (apparent q, 2H, J=6.7 Hz), 4.58 (s,2H), 3.82 (b s 1H), 3.70 (b s, 1H), 3.36 (s, 3H), 3.23 (s, 3H), 2.46 (m,1H), 2.30-2.17 (m, 2H), 0.98 (s, 3H), 0.92 (s, 3H); ¹³C NMR (CDCl₃) δ162.1, 100.0, 94.4, 77.1, 71.5, 58.5, 56.2, 55.3, 55.1, 43.5, 40.6,36.2, 36.1, 33.1, 32.6, 32.3, 31.7, 29.1, 28.0, 26.0, 23.9, 19.4, 14.1.

(3α,5α,11β,17β)-11-Methoxy-3-(methoxymethoxy)-androstane-17-methanol(31)

To compound 30 (450 mg, 1.24 mmol) in THF (5 mL) was added 9-BBN (6 mL,0.5 M in THF) and the reaction was stirred at room temperature for 15 h.After cooling to 0° C., 30% hydrogen peroxide (15 mL) and 3 M aqueousNaOH (15 mL) were added and stirring was continued at room temperaturefor 2 h. Water (80 mL) was added and the product extracted into Et₂O.The extract was washed with brine, dried and concentrated to give aviscous liquid which was purified by flash column chromatography (silicagel eluted with 20-40% EtOAc in hexanes) to give compound 31 as an oil(391 mg, 83%): IR v_(max) 3413, 2924, 2871, 144, 1368, 1382 cm⁻¹; ¹H NMR(CDCl₃) δ 4.64 (apparent q, 2H, J=7.5 Hz), 3.81 (b s, 1H), 3.66 (m, 1H),3.61 (b s, 1H), 3.51 (m, 1H), 3.35 (s, 3H), 3.18 (s, 3H), 2.31 (m, 1H),0.96 (s, 3H), 0.78 (s, 3H); ¹³C NMR (CDCl₃) δ 94.4, 77.1, 71.5, 64.5,58.4, 57.8, 55.4, 55.1, 53.3, 41.2, 40.5, 39.4, 36.0, 33.0, 32.6, 32.5,31.5, 28.0, 26.0, 25.0, 24.3, 14.0, 13.5.

(3α,5α,11β,17β)-17-Hydroxymethyl-11-methoxy-3-(methoxymethoxy)-androstan-18-oicacid-γ-lactone (32)

Compound 32 was prepared as an oil in 34% yield from compound 31 usingthe procedure described for the preparation of compound 5 from compound4. Compound 32 had: IR v_(max) 2927, 1771, 1446, 1368, 1278 cm⁻¹; ¹H NMR(CDCl₃) δ 4.64 (apparent q, 2H, J=6.7 Hz), 4.32 (dd, 1H, J=9.0 Hz, J=4.3Hz), 3.99 (m, 1H), 3.82 (b s, 1H), 3.67 (b s, 1H), 3.35 (s, 3H), 3.15(s, 3H), 2.76 (m, 1H), 2.52 (m, 1H), 2.22 (m, 1H), 2.07 (m, 1H), 1.04(s, 3H), 0.89 (m, 2H); ¹³C NMR (CDCl₃) δ 177.7, 94.4, 75.7, 71.5, 70.4,57.9, 55.6, 55.5, 55.0, 51.0, 46.8, 40.5, 36.1, 33.0, 32.9, 32.8, 29.9,29.8, 27.8, 26.2, 26.0, 14.1.

1-[(3α,5α,11β,17β)-17-Hydroxymethyl-1′-methoxy-3-(methoxymethoxy)-18-norandrostan-13-yl]ethanone(33)

Compound 33 (65 mg, 57%) was prepared as an oil from compound 32 usingthe procedure described for the preparation of compound 6 from compound5. Compound 33 had: IR v_(max) 3447, 2928, 1694, 1445, 1349 cm⁻¹; ¹H NMR(CDCl₃) δ 4.63 (apparent q, 2H, J=7.1 Hz), 3.81 (b s, 1H), 3.45-3.60 (m,2H), 3.38 (m, 1H), 3.34 (s, 3H), 3.02 (s, 3H), 2.99 (m, 1H), 2.19 (m,1H), 2.16 (s, 3H), 0.89 (s, 3H), 0.77 (m, 1H); ¹³C NMR (CDCl₃) δ 212.4,94.4, 76.0, 71.4, 64.8, 59.0, 58.6, 56.7, 55.3, 55.1, 52.6, 41.7, 40.2,35.8, 33.2, 32.9, 32.6, 32.0, 29.9, 27.9, 26.0, 25.2, 24.1, 13.7.

(3α,5α,11β,17β)-13-Acetyl-11-methoxy-3-(methoxymethoxy)-18-norandrostane-17-carboxaldehyde(34)

Compound 34 was prepared from compound 33 using the procedure describedfor the preparation of compound 7 from compound 6. Compound 34 wasimmediately converted without characterization to compound 35.

1-[(3α,5α,11β)-11-Methoxy-3-(methoxymethoxy)-18-norpregn-20-en-13-yl]ethanone(35)

Compound 35 (40 mg, 66%) was obtained as an oil from compound 34 usingthe procedure described for the preparation of compound 8 from compound7. Compound 35 had: IR v_(max) 2927, 1699, 1444, 1368 cm⁻¹; ¹H NMR(CDCl₃) δ 5.71 (m, 1H), 5.03 (m, 2H), 4.65 (apparent q, 2H, J=6.7 Hz),3.82 (b s, 1H), 3.60 (b s, 1H), 3.36 (s, 3H), 3.17 (s, 3H), 2.80 (dd,1H, J=13.7 Hz, J=3.1 Hz), 2.21 (m, 2H), 1.95 (s, 3H), 0.89 (s, 3H), 0.75(dd, 1H, J=11.4 Hz, J=2.8 Hz); ¹³C NMR (CDCl₃) δ 209.8, 138.9, 115.2,94.5, 76.5, 71.5, 59.2, 57.6, 56.4, 55.1, 54.9, 40.4, 38.5, 36.0, 33.4,32.9, 32.6, 31.6, 29.51, 28.0, 27.6, 26.1, 24.3, 13.8.

1-[(3α,5α,11β)-3-Hydroxy-11-methoxy-18-norpregn-20-en-13-yl]ethanone(36, KK-144)

Compound 36 (26 mg, 85%) was prepared from compound 35 as a white solidusing the procedure described for the preparation of compound 9 fromcompound 8. Compound 36 had: mp 127-129° C.; [α]_(D) ²³ −32 (c 0.03,CHCl₃); IR v_(max) 3401, 2925, 1698, 1593, 1444 cm⁻¹; ¹H NMR (CDCl₃) δ5.72 (m, 1H), 5.05 (m, 2H), 4.05 (b s, 1H), 3.62 (b s, 1H), 3.18 (s,3H), 2.82 (dd, 1H, J=14.1 Hz, J=3.6 Hz), 2.22 (m, 2H), 1.96 (s, 3H),0.89 (s, 3H); ¹³C NMR (CDCl₃) δ 209.8, 138.9, 115.2, 76.5, 66.4, 59.9,59.2, 57.6, 56.5, 54.9, 39.8, 38.5, 36.3, 35.3, 32.7, 32.6, 31.6, 29.5,28.7, 27.9, 27.7, 24.4, 13.6. Anal. (C₂₃H₃₆O₃): C, 76.62%; H, 10.06%.Found: C, 76.68%; H, 9.93%.

In accordance with Scheme 4, the following compounds were prepared,using methods generally known in the art and as outlined below.

(5α)-19-Hydroxy-androstane-3,17-dione, cyclic bis-(1,2-ethanediylacetal) (37)

Compound 37 was prepared as described previously (see, Santaniello &Caspi, “Reduction of certain steroidal 19-sulfonic esters with metalhydrides,” J. of Ster. Biochem., Vol. 7(3), pages 223-227 (1976)).

(5α)-19-Methoxy-androstane-3,17-dione, cyclic bis-(1,2-ethanediylacetal) (38)

A mixture of compound 37 (430 mg, 1.1 mmol), NaH (200 mg, 5 mmol) andTHF (10 mL) was heated at reflux for 2 h under N₂. The reaction mixturewas cooled to room temperature, and methyl iodide (2 mL, 32 mmol) wasadded and the mixture was stirred at room temperature for 13 h. Thereaction mixture was cooled to 0° C. and excess NaH was consumed byadding MeOH (2 mL). Water (100 mL) was added and the product wasextracted into EtOAc (80 mL×3). The combined organic extracts werewashed with brine, dried and concentrated to give a colorless liquid.The crude product was purified by flash column chromatography (silicagel eluted with 15-20% EtOAc in hexanes) to give product 38 as acolorless liquid (440 mg, 99%): IR v_(max) 2923, 1457, 1378, 1306, 1210cm⁻¹; ¹H NMR δ 3.89 (s, 4H), 3.87-3.82 (m, 4H), 3.47 (d, 1H, J=10.0 Hz),3.39 (d, 1H, J=9.9 Hz), 3.25 (s, 3H), 0.82 (s, 3H); ¹³C NMR δ 119.3,109.2, 71.0, 65.0, 64.5, 64.0, 59.0, 54.0, 50.4, 46.0, 43.8, 38.9, 38.4,36.2, 34.1, 31.5, 31.1, 31.0 (2×C), 29.6, 28.1, 22.6, 21.7, 14.4. Anal.(C₂₄H₃₈O₅): C, 70.90%; H, 9.42%. Found: C, 71.17%; H, 9.53%.

(5α)-19-Methoxy-androstane-3,17-dione (39)

A mixture of compound 38 (400 mg, 0.98 mmol), PTSA (100 mg), acetone (8mL) and water (0.5 mL) was stirred at room temperature for 14 h. Thereaction was neutralized with aqueous NaHCO₃ and the acetone was removedunder reduced pressure. Water (80 mL) was added and the product wasextracted into EtOAc (60 mL×3). The combined EtOAc extracts were driedand concentrated to give a white solid which was purified by flashcolumn chromatography (silica gel eluted with 20-30% EtOAc in hexanes)to yield product 39 (230 mg, 73%): mp 94-96° C.; IR v_(max) 2918, 1738,1712, 1452, 1407, 1373, 1270, 1248, 1220, 1202, cm⁻¹; ¹H NMR δ 3.60 (d,1H, J=11.0 Hz), 3.57 (d, 1H, J=11.0 Hz), 3.26 (s, 3H), 2.50-0.74 (m),0.82 (s, 3H); ¹³C NMR δ 220.5, 211.7, 71.7, 59.0, 53.9, 51.3, 47.6,46.1, 44.7, 38.9, 38.5, 35.6, 35.3, 34.2, 31.5, 30.3, 28.1, 21.5, 21.3,13.7. HRMS Calcd for (C₂₀H₃₀O₃): 318.2195. Found: 318.2180.

(3α,5α)-3-Hydroxy-19-methoxy-androstan-17-one (40)

A 1 M K-Selectride solution in THF (2 mL, 2 mmol, 3 eq) was added to acold solution (−78° C.) of compound 39 (210 mg, 0.66 mmol) in THF (5 mL)and the reaction was stirred at −78° C. for 1.5 h. The reaction wasstopped by adding a few drops of acetone and then allowed to warm toroom temperature. 3 N aqueous NaOH (10 mL) followed by 30% aqueous H₂O₂(10 mL) was added and the reaction was stirred at room temperature for1.5 h. The product was extracted into EtOAc (3×60 mL) and the combinedEtOAc extracts were washed with brine, dried, and concentrated to givean off-white solid which was purified by flash column chromatography(silica gel eluted with 20-40% EtOAc in hexanes). Product 40 (142 mg,67%) had: mp 172-174° C.; IR v_(max) 3436, 2921, 1738, 1453, 1406, 1372,1248, 1203 cm⁻¹; ¹H NMR δ 4.05 (b s, 1H), 3.48 (d, 1H, J=9.9 Hz), 3.38(d, 1H, J=10.2 Hz), 3.25 (s, 3H), 2.39 (dd, 1H, J=19.3 Hz, 8.8 Hz, 1H),2.2.10-0.70 (m), 0.84 (s, 3H); ¹³C NMR δ 221.5, 71.1, 66.1, 59.0, 54.6,51.7, 47.8, 39.6, 39.2, 36.0, 35.7, 35.5, 31.8, 30.7, 29.2, 27.9, 27.1,21.6, 21.1, 13.8. Anal. (C₂₀H₃₂O₃): C, 74.96%; H, 10.06%. Found: C,74.91%; H, 9.86%.

(3α,5α)-19-Methoxy-3-(methoxymethoxy)-androstan-17-one (41)

To a solution of compound 40 (800 mg, 2.5 mmol) in DCM (20 mL) was addedchloromethyl methyl ether (302 mg, 3.75 mmol) andN,N-diisopropylethylamine (774 mg, 6 mmol) at room temperature. Themixture was stopped by water addition after 16 h and the productextracted into EtOAc (100 mL×2). The combined extracts were washed withbrine, dried and concentrated. The residue was purified by columnchromatography (silica gel eluted with 25% EtOAc in hexanes) to giveproduct 41 as an oil (900 mg, 100%): IR v_(max) 2921, 1740 cm⁻¹; ¹H NMR(CDCl₃) δ 4.65 (dd, 1H, J=6.6 Hz, J=10.9 Hz), 3.86-3.84 (m, 1H), 3.52(d, 1H, J=10.2 Hz), 3.43 (d, 1H, J=9.8 Hz), 3.35 (s, 3H), 3.28 (s, 3H),0.86 (s, 3H); ¹³C NMR (CDCl₃) δ 221.4, 94.5, 71.3, 71.2, 59.1, 55.1,54.6, 51.7, 47.9, 39.9, 39.4, 35.8, 35.5, 34.0, 31.9, 30.8, 28.0, 27.7,26.5, 21.7, 21.2, 13.9.

(3α,5α)-19-Methoxy-3-(methoxymethoxy)-17-methylene-androstane (42)

To a stirred suspension of methyltriphenylphosphonium bromide (7.14 g,20 mmol) in THF (60 mL) was added solid potassium t-butoxide (2.12 g, 19mmol) and the mixture was heated at reflux for 1 h under a nitrogenatmosphere. A THF solution (15 mL) of compound 41 (740 mg, 2.03 mmol)was added to the resulting yellow refluxing methylenetriphenylphosphorane solution using a syringe. The reaction mixture wascontinued at reflux for 3 h. The completion of reaction was confirmed bymonitoring by TLC analysis. The reaction mixture was cooled to roomtemperature, water was added and the product extracted into EtOAc. Theextract was dried and concentrated to give an oil which was purified bycolumn chromatography (silica gel eluted with 2-20% EtOAc in hexanes) togive compound 42 as an oil (680 mg, 92%): IR v_(max) 2921, 1655, 1447,1371, 1204 cm⁻¹; ¹H NMR (CDCl₃) δ 4.67 (apparent q, 2H, J=6.6 Hz), 4.62(m, 2H), 3.88 (b s, 1H), 3.49 (apparent q, 2H, J=9.8 Hz) 3.37 (s, 3H),3.31 (s, 3H), 2.45 (m, 1H), 2.21 (m, 1H), 1.98 (m, 1H), 0.80 (s, 3H);¹³C NMR (CDCl₃) δ 162.1, 100.6, 94.4, 71.4, 71.3, 59.1, 55.1, 54.7,54.6, 44.2, 40.0, 39.4, 36.0, 35.9, 34.0, 31.7, 29.3, 28.2, 27.5, 26.6,24.1, 21.9, 18.6.

(3α,5α,17β)-19-Methoxy-3-(methoxymethoxy)-androstane-17-methanol (43)

To a solution of compound 42 (680 mg, 1.87 mmol) in THF (5 mL) was added9-BBN (8 mL, 0.5 M solution in THF) and the reaction was stirred at roomtemperature for 15 h, them cooled to 0° C. 30% Hydrogen peroxide (15 mL)and 3 M aqueous NaOH (15 mL) was added to the cold solution and stirringwas continued at room temperature for 2 h. Water (80 mL) was added andthe product was extracted into Et₂O. The extract was washed with brine,dried and concentrated to give a viscous liquid which wash purified bycolumn chromatography (silica gel eluted with 20-40% EtOAc in hexanes)to give compound 43 as an oil (620 mg, 87%): IR v_(max) 3496, 2936,1455, 1365, 1306 cm⁻¹; ¹H NMR (CDCl₃) δ 4.65 (apparent q, 2H, J=7.0 Hz),3.86 (b s, 1H), 3.68 (dd, 1H, J=7.5 Hz, J=4.7 Hz), 3.50 (dd, 1H, J=7.5Hz, J=4.7 Hz), 3.46 (apparent q, 1H, J=10.2 Hz), 3.35 (s, 3H), 3.28 (s,3H), 0.64 (s, 3H); ¹³C (CDCl₃) NMR δ 94.4, 71.4, 71.3, 64.6, 59.1, 56.2,55.1, 54.8, 53.0, 41.9, 39.9, 39.3, 39.1, 35.6, 34.0, 31.9, 28.2, 27.6,26.6, 25.6, 24.5, 21.7, 12.7.

(3α,5α,17β)-17-Hydroxymethyl-19-methoxy-3-(methoxymethoxy)-androstan-18-oicacid, γ-lactone (44)

Compound 44 (110 mg, 36%) was prepared as an oil in 34% yield fromcompound 43 using the procedure described for the preparation ofcompound 5 from compound 4. Compound 44 had: IR v_(max) 2924, 1757, 1445cm⁻¹; ¹H NMR (CDCl₃) δ 4.64 (apparent q, 2H, J=7.0 Hz), 4.30 (m, 1H),4.06 (m, 1H), 3.86 (b s, 1H), 3.51 (apparent q, 2H, J=10.2 Hz), 3.35 (s,3H), 3.30 (s, 3H); ¹³C NMR (CDCl₃) δ 179.6, 94.4, 72.2, 71.4, 70.4,58.8, 55.2, 55.1, 53.6, 53.5, 45.2, 39.9, 39.4, 34.0, 33.9, 32.1, 31.9,31.3, 27.9, 27.4, 27.3, 26.6, 21.3.

1-[(3α,5α,17β)-17-Hydroxymethyl-19-methoxy-3-(methoxymethoxy)-18-norandrostan-13-yl]ethanone(45)

Compound 45 (60 mg, 53%) was prepared as an oil from compound 45 usingthe procedure described for the preparation of compound 6 from compound5. Compound 45 had: IR v_(max) 3468, 2926, 2871, 1695, 1446, 1372 cm⁻¹;¹H NMR (CDCl₃) δ 4.65 (apparent q, 2H, J=7.1 Hz), 3.85 (b, 1H), 3.60 (m,2H), 3.36 (s, 2H), 3.35 (s, 3H), 3.21 (s, 3H), 2.64 (m, 1H), 2.20 (s,3H); ¹³C NMR (CDCl₃) δ 214.3, 94.4, 71.3, 70.6, 63.8, 61.0, 58.9, 57.7,55.1, 54.8, 53.0, 39.9, 39.3, 36.5, 33.9, 31.8, 30.1, 28.0, 27.1, 26.4,25.7, 24.9, 24.4.

(3α,5α,17β)-13-Acetyl-19-methoxy-3-(methoxymethoxy)-18-norandrostane-17-carboxaldehyde(46)

Compound 46 was prepared from compound 45 using the procedure describedfor the preparation of compound 7 from compound 6. Compound 34 wasimmediately converted without characterization to compound 47.

1-[(3α,5α)-19-Methoxy-3-(methoxymethoxy)-18-norpregn-20-en-13-yl]ethanone(47)

Compound 47 (30 mg, 50%) was prepared from compound 46 as an oil usingthe procedure described for the preparation of compound 8 from compound7. Compound 47 had: IR v_(max) 2926, 1698, 1446, 1357 cm⁻¹; ¹H NMR(CDCl₃) δ 5.62 (m, 1H), 5.01-5.10 (m, 2H), 4.67 (apparent q, 2H, J=7.1Hz), 3.88 (b s, 1H), 3.39 (s, 2H), 3.38 (s, 3H), 3.22 (s, 3H), 2.42 (m,1H), 2.26 (m, 1H), 2.05 (s, 3H); ¹³C NMR (CDCl₃) δ 213.1, 138.7, 115.6,94.5, 71.3, 70.6, 63.0, 58.9, 57.3, 55.14, 55.01, 54.8, 40.0, 39.4,36.5, 35.0, 34.0, 31.9, 30.3, 28.2, 28.1, 27.1, 26.5, 25.2, 24.3.

1-[(3α,5α)-3-Hydroxy-19-methoxy-18-norpregn-20-en-13-yl]ethanone (48,KK-145)

Compound 48 (22 mg, 81%) was prepared from compound 47 as a white solidusing the procedure described for the preparation of compound 9 fromcompound 8. Compound 48 had: mp 124-126° C.; [α]_(D) ²³ −23.1 (c 0.13,CHCl₃); IR v_(max) 3325, 2924, 2868, 1697, 1638, 1446, 1358, 1225 cm⁻¹;¹H NMR (CDCl₃) δ 5.62 (m, 1H), 5.01-5.12 (m, 2H), 4.09 (b s, 1H), 3.37(s, 2H), 3.21 (s, 3H), 2.41 (m, 1H), 2.27 (m, 1H), 2.05 (s, 3H); ¹³C NMR(CDCl₃) δ 213.1, 138.6, 115.6, 70.4, 66.4, 63.0, 58.9, 57.2, 55.0, 54.8,39.6, 39.3, 36.6, 36.1, 35.1, 31.9, 30.3, 29.3, 28.1, 28.0, 26.5, 25.2,24.3. HRMS (FAB) Calcd for (C₂₃H₃₆O₃Na): 383.2562 Found: 383.2566.

In accordance with Scheme 5, the following compounds were prepared,using methods generally known in the art and as outlined below.

Androsterone (49)

Compound 49 is commercially available and was purchased from theSigma-Aldrich Chemical Co. (St. Louis, Mo.).

(3α,5α)-17-Methylene-androstan-3-ol (50)

Compound 50 was prepared as described previously (see, Ruzicka, et al.,“Steroids and sex hormones. CXXXIX. The relation between constitutionand odor of steroids. Methylandrostane and allopregnane derivatives,”Helvetica Chimica Acta, Vol. 30, pages 867-878 (1947)).

(3α,5α)-3-(Methoxymethoxy)-17-methylene-androstane (51)

Chloromethyl methyl ether (0.43 mL, 5.63 mmol) was added to a solutionof compound 50 (540 mg, 1.88 mmol) and N,N-diisopropyl ethylamine (1.63mL, 9.38 mmol) in CH₂Cl₂ (50 mL). The resultant solution was stirred atroom temperature for 20 h. The solvent was partially removed and theresidue was purified by column chromatography (silica gel;hexanes/EtOAc, 30:1) to give compound 51 (590 mg, 95%) as a white solid:mp 73-75° C.; IR v_(max) 2922, 1655, 1447 cm⁻¹; ¹H NMR (CDCl₃) δ 0.77(s, 3H), 0.81 (s, 3H), 2.22 (m, 1H), 2.47 (m, 1H), 3.37 (s, 3H), 3.83(m, 1H), 4.62 (m, 2H), 4.66 (m, 2H); ¹³C NMR (CDCl₃) δ 162.1, 100.5,94.5, 71.6, 55.1, 54.5 (2×C), 44.1, 39.8, 36.0, 35.7, 35.4, 33.6, 32.8,31.8, 29.4, 28.5, 26.3, 24.1, 20.6, 18.5, 11.4. Anal. (C₂₂H₃₆O₂): C,79.46; H, 10.91. Found: C, 79.26; H, 11.13.

(3α,5α,17β)-3-(Methoxymethoxy)-androstane-17-methanol (52)

BH₃.THF (1.0 M in THF, 3.73 mL, 3.73 mmol) was added to compound 51 (620mg, 0.19 mmol) in anhydrous THF (30 mL) under N₂ at 0° C. The resultantsolution was stirred at room temperature for 3.5 h and cooled to 0° C.Aqueous NaOH (3 N, 2.6 mL) was added carefully to the reaction followedby 30% H₂O₂ (2.6 mL). The reaction mixture was stirred at ambienttemperature overnight and extracted with EtOAc. The combined EtOAcextracts were washed with brine until neutral pH and dried. Aftersolvent removal under reduced pressure, the residue was purified bycolumn chromatography (silica gel; hexanes/EtOAc, 6:1) to give compound52 (560 mg, 86%). It was contaminated with 10% 17α-methanol epimer andwas used without further purification. Compound 52 was obtained asviscous oil: IR v_(max) 3401, 2922, 1446 cm⁻¹; ¹H NMR (CDCl₃) δ 0.64 (s,3H), 0.79 (s, 3H), 3.37 (s, 3H), 3.54 (m, 1H), 3.70 (m, 1H), 3.83 (m,1H), 4.66 (m, 2H); ¹³C NMR (CDCl₃) δ 11.4, 12.6, 20.5, 24.5, 25.5, 26.3,28.5, 32.0, 32.8, 33.6, 35.2, 35.9, 38.8, 39.7, 41.9, 53.0, 54.5, 55.1,56.0, 64.6, 71.6, 94.5.

(3α,5α,17β)-17-Hydroxymethyl-3-(methoxymethoxy)-androstan-18-oic acid,γ-lactone (53)

I₂ (530 mg, 2.09 mmol) and Pb(OAc)₄ (2.07 g, 4.67 mmol) was added to therefluxing solution of compound 52 (460 mg, 1.31 mmol) in cyclohexane (70mL) under N₂. The reaction mixture was refluxed and irradiated with a300 W tungsten lamp. After 80 min, Pb(OAc)₄ (1.15 g, 2.66 mmol) wasadded again. After the reaction mixture was heated for another 50 min,it was filtered hot and the residue was washed with additionalcyclohexane. The combined cyclohexane solution was evaporated to yieldan oil, which was dissolved in acetone (50 mL) and Jones reagent wasadded dropwise at 0° C. until an orange color persisted. The resultantmixture was stirred at 0-5° C. for 30 min. 2-Propanol was added toconsume excess oxidant and the acetone was removed under reducedpressure. The residue obtained was dissolved in EtOAc (50 mL), washedwith water to neutral pH, and dried. The solvent was removed and theresidue was purified by column chromatography (silica gel;hexanes/EtOAc, 20:1) to give compound 53 (250 mg, 53%) as whitecrystals: mp 144-146° C.; IR v_(max) 2927, 1754 cm⁻¹; ¹H NMR (CDCl₃) δ0.87 (s, 3H), 2.08 (m, 2H), 2.31 (m, 2H), 3.37 (s, 3H), 3.84 (m, 1H),4.08 (d, 1H, J=9.0 Hz), 4.32 (dd, 1H, J=5.1, 9.0 Hz), 4.67 (m, 2H); ¹³CNMR δ 179.5, 94.5, 72.3, 71.6, 55.4, 55.1, 53.5, 53.5, 45.3, 39.7, 36.0,33.6, 33.5, 33.0, 32.3, 31.7, 31.4, 28.3, 27.4, 26.3, 20.1, 11.4. Anal.(C₂₂H₃₄O₄): C, 72.89; H, 9.45. Found: C, 72.73; H, 9.52.

1-[(3α,5α,17β)-17-Hydroxymethyl-3-(methoxymethoxy)-18-norandrostan-13-yl]ethanone(54)

CH₃Li (1.6 M in Et₂O, 4.3 mL, 6.91 mmol) was added to compound 53 (500mg, 1.38 mmol) in Et₂O (100 mL) under N₂ and refluxed for 30 min. Aftercooling to room temperature, water was added carefully to stop thereaction. The Et₂O was washed with 5% aqueous HCl, water and dried. Thesolvent was removed and the residue was purified by columnchromatography (silica gel; CH₂Cl₂/EtOAc, 10:1) to give compound 54 (450mg, 86%) as white solid: mp 109-113° C.; IR v_(max) 3498, 2927, 1694cm⁻¹; ¹H NMR (CDCl₃) δ 0.69 (s, 3H), 2.21 (s, 3H), 2.68 (m, 1H), 3.37(s, 3H), 3.58 (m, 2H), 3.82 (m, 1H), 4.66 (m, 2H); ¹³C NMR (CDCl₃) δ213.9, 94.5, 71.6, 63.9, 61.0, 57.6, 55.1, 54.8, 53.0, 39.7, 36.3, 36.2,35.8, 33.5, 32.8, 31.9, 30.3, 28.3, 26.2, 25.7, 24.8, 23.0, 11.4. Anal.(C₂₃H₃₈O₄): C, 72.98; H, 10.12. Found: C, 72.88; H, 10.20.

(3α,5α,17β)-13-Acetyl-3-(methoxymethoxy)-18-norandrostane-17-carboxaldehyde(55)

Compound 54 (330 mg, 0.87 mmol) in DMSO (1 mL) was added to the solutionof iodoxybenzoic acid (400 mg, 1.43 mmol) in DMSO (2.5 mL) and stirredat room temperature for 90 min. Water (30 mL) was added and theprecipitate obtained by filtration was washed thoroughly with EtOAc. TheEtOAc filtrate was washed with water and dried. The solvent was removedand the residue was purified by flash column chromatography (silica geleluted with hexanes/EtOAc, 7:1) to give compound 55 (300 mg, 91%) as amixture of 17α- and 17β-carboxaldehydes in the ratio of 1:4 which wasused without further separation or purification.

1-[(3α,5α)-3-(Methoxymethoxy)-18-norpregn-20-en-13-yl]ethanone (56)

A mixture of KOBu^(t) (134 mg, 1.20 mmol) and methyltriphenylphosphoniumbromide (570 mg, 1.60 mmol) in anhydrous THF (20 mL) was stirred at roomtemperature for 30 min under N₂ and compound 55 (300 mg, 0.80 mmol) inTHF (5 mL) was added. The mixture was stirred at room temperature for 20min and water (20 mL) was added. The product was extracted into EtOAc.The EtOAc was washed with water, brine and dried. Solvent removal underreduced pressure gave a residue which was purified by columnchromatography (silica gel eluted with hexanes/EtOAc, 20:1) to givecompound 12 (300 mg, 99%), as a mixture of 17α and 17β diasteromers inthe ratio of 5:2. Pure compound 56 (155 mg, 52%) was obtained byrecrystallization from hexanes as colorless crystals: mp 115-116° C.; IRv_(max) 2927, 1698 cm⁻¹; ¹H NMR (CDCl₃) δ 0.69 (s, 3H), 2.04 (s, 3H),2.27 (dd, 1H, J=8.7 Hz, J=18.3 Hz), 2.45 (m, 1H), 3.37 (s, 3H), 3.82 (m,1H), 4.66 (m, 2H), 5.06 (m, 2H), 5.63 (m, 1H); ¹³C NMR (CDCl₃) δ 212.7,138.6, 115.6, 94.4, 71.5, 62.9, 57.2, 55.1, 55.0, 54.8, 39.7, 36.1,35.8, 34.7, 33.5, 32.8, 31.9, 30.3, 28.3, 28.1, 26.2, 25.1, 22.8, 11.5,11.5, 22.8, 25.1, 26.2, 28.1, 28.3, 30.3, 31.9, 32.8, 33.5, 34.7, 35.8,36.1, 39.7, 54.8, 55.0, 55.1, 57.2, 62.9, 71.5, 94.4, 115.6, 138.6,212.7. Anal. (C₂₄H₃₈O₃): C, 76.96; H, 10.23. Found: C, 77.14; H, 10.19.

1-[(3α,5α)-3-Hydroxy-18-norpregn-20-en-13-yl]ethanone (57, XJ-99)

Compound 57 (24 mg, 97%) was prepared from compound 56 as a white solidusing the procedure described for the preparation of compound 9 fromcompound 8. Compound 57 was obtained as white crystals: mp 178-179.5° C.(from hexanes); IR v_(max) 3306, 2927, 1697 cm⁻¹; ¹H NMR (CDCl₃) δ 0.68(s, 3H), 2.05 (s, 3H), 2.27 (m, 1H), 2.45 (m, 1H), 4.03 (m, 1H), 5.06(m, 2H), 5.63 (m, 1H); ¹³C NMR (CDCl₃) δ 212.8, 138.7, 115.6, 66.5,63.0, 57.2, 55.0, 54.8, 39.1, 36.2, 36.1, 35.8, 34.7, 32.2, 32.0, 30.4,28.9, 28.3, 28.2, 25.1, 22.9, 11.3. Anal. (C₂₂H₃₄O₂): C, 79.95; H,10.37. Found: C, 80.18; H, 10.54.

1-[(3α,5α)-3-Hydroxy-18-norpregnan-13-yl]ethanone (58, XJ-100)

Compound 57 (30 mg, 0.91 mmol) was dissolved in EtOAc (10 mL) andhydrogenated (60 psi, H₂, 5% Pd/C, 10 mg) in a Parr hydrogenationapparatus for 4 h. The reaction mixture was filtered through a pad ofCelite 545 to remove catalyst and the solvent was removed under reducedpressure. The product was purified by flash column chromatography(silica gel eluted with hexanes/EtOAc, 3:1) to give compound 58 (29 mg,96%) as white solid: mp 182-184° C. (from Et₂O/hexanes); IR v_(max)3306, 2927, 1694 cm⁻¹; ¹H NMR (CDCl₃) δ 0.67 (s, 3H), 0.91 (t, 3H, J=2.9Hz), 2.09 (s, 3H), 2.50 (m, 1H), 4.04 (m, 1H); ¹³C NMR (CDCl₃) δ 213.6,66.5, 61.7, 57.5, 54.9, 52.8, 39.1, 36.3, 36.1, 35.8, 35.3, 32.2, 31.9,30.4, 28.9, 28.6, 28.3, 24.9, 24.6, 23.0, 13.6, 11.3. Anal. (C₂₂H₃₆O₂):C, 79.46; H, 10.91. Found: C, 79.21; H, 10.78.

In accordance with Scheme 6, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3α,5α,20R)-Pregnane-3,20-diol, 3-acetate (59)

Product 59 was prepared as described in the literature and had: ¹H NMR(CDCl₃) δ 5.08 (m, 1H), 3.73 (m, 1H), 2.05 (s, 3H), 1.13 (d, 3H, J=6Hz), 0.80 (s, 3H), 0.75 (s, 3H)(see, Stastna, et al., “Stereoselectivityof sodium borohydride reduction of saturated steroidal ketones utilizingconditions of Luche reduction,” Steroids, Vol. 75(10), pages 721-725(2010)).

(3α,5α,20R)-3-(Acetyloxy)-20-hydroxy-pregnan-18-oic acid, γ-lactone (60)

Compound 59 (400 mg, 1.1 mmol) was converted to compound 60 (270 mg,63%) according to procedure used to prepare compound 53. Compound 60had: IR v_(max) 2935, 2856, 1735, 1449, 1366, 1238 cm⁻¹; ¹H NMR (CDCl₃)δ 4.69 (m, 1H), 3.35 (q, 1H, J=6.6 Hz), 2.02 (s, 3H), 1.36 (d, 1H, J=6.6Hz), 0.91 (s, 3H); ¹³C NMR (CDCl₃) δ 179.2, 170.6, 82.3, 73.5, 55.9,53.5, 53.3, 50.5, 44.5, 36.7, 35.5, 34.9, 33.8, 33.0, 32.9, 32.2, 28.2,27.3, 27.2, 22.5, 21.3, 20.8, 12.1.

(3α,5α,20R)-3,20-Dihydroxy-pregnan-18-oic acid, γ-lactone (61)

Compound 60 (254 mg, mmol) was dissolved in MeOH (30 ml) and 2% aqueousNa₂CO₃ was added. The reaction was refluxed overnight, cooled to roomtemperature and the MeOH removed. Water was added and the productextracted into EtOAc. The EtOAc was washed with brine, dried and aftersolvent removal product 61 was obtained as a pale yellow solid (240 mg,%). Compound 61 recrystallized from CH₂Cl₂ and hexanes had: mp 214-215°C.; IR v_(max) 3494, 2943, 2927, 1733, 1447, 1346, 1239 cm⁻¹; ¹H NMR(CDCl₃) δ 4.35 (q, 1H, J=6.6 Hz), 4.06 (b s, 1H), 1.37 (d, 3H, 6.6 Hz),0.87 (3, 3H); ¹³C NMR (CDCl₃) δ 179.4, 82.4, 66.5, 56.2, 53.7, 53.6,50.7, 39.0, 36.2, 35.8, 35.1, 33.11, 33.06, 32.32, 32.28, 29.0, 28.3,27.3, 22.6, 20.5, 11.2. Anal. (C₂₁H₃₂O₃): C, 75.86; H, 9.70. Found: C,75.68; H, 9.48.

(3α,5α,20R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-20-hydroxy-pregnan-18-oicacid, γ-lactone (62)

Compound 61 (220 mg, 0.66 mmol), TBDMSCl (220 mg, 1.46 mmol) andimidazole (190 mg) were dissolved in DMF (4 mL) and stirred overnight atroom temperature. The DMF was removed under high vacuum, water was addedand the product extracted into EtOAc. The EtOAc was washed with brine,dried and after solvent removal crude product (310 mg) was obtained.Flash column chromatography (silica gel eluted with 5% EtOAc in hexanes)gave compound 62 as a white solid (260 mg, 88%): IR v_(max) 2928, 2856,1761, 1445, 1372, 1252 cm⁻¹; ¹H NMR (CDCl₃) δ 4.32 (q, 1H, J=6.6 Hz),3.95 (m, 1H), 1.35 (d, 3H, J=6.6 Hz), 0.87 (s, 3H), 0.82 (s, 3H), 0.0(s, 6H); ¹³C NMR (CDCl₃) δ 179.4, 82.4, 66.9, 56.4, 53.8, 50.9, 39.1,36.8, 36.2, 35.2, 33.3, 33.2, 32.6, 32.5, 29.7, 28.4, 27.3, 25.9, 22.7,20.6, 18.1, 11.5, −4.8.

(3α,5α,20R)-13-Acetyl-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-18-norpregnan-20-ol(63)

Compound 62 (210 mg, 0.47 mmol) was converted into compound 63 (230 mg)according to the procedure used to prepare compound 54. Compound 63 wasa white solid: IR v_(max) 3440, 2855, 2839, 1680, 1470, 1461, 1444,1369, 1361, 1247 cm⁻¹; ¹H NMR (CDCl₃) δ 3.93 (m, 1H), 3.46 (m, 1H), 2.83(m, 1H), 2.30 (s, 3H), 1.13 (d, 3H, J=6.1 Hz), 0.87 (s, 3H), 0.72 (s,3H), 0.0 (s, 6H).

(3α,5α)-13-Acetyl-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-18-norpregnan-20-one(64)

Compound 63 (190 mg, 0.41 mmol) was dissolved in acetone (20 mL) at −20°C. and Jones reagent (0.8 mL) was added. After stirring for 1 h,2-propanol (1 mL) was added and after 15 min the solvent was removed.Water was added and the product extracted into EtOAc. The EtOAc waswashed with brine, dried and the solvent removed. The product waspurified by flash column chromatography (silica gel eluted with 20%EtOAc in hexanes) to give compound 64 (120 mg, 63%): IR v_(max) 2928,2857, 1710, 1361, 1251 cm⁻¹; 3.93 (m, 1H), 2.69-2.62 (m, 2H), 2.15 (s,3H), 2.06 (s, 3H), 0.87 (s, 9H), 0.65 (s, 3H), 0.0 (s, 6H); ¹³C NMR(CDCl₃) δ 211.8, 209.0, 66.8, 64.4, 61.7, 57.9, 54.6, 39.0, 36.6, 36.3,36.03, 35.99, 32.4, 32.0, 30.8, 30.1, 29.6, 28.3, 25.8, 25.6, 24.9,22.8, 18.1, 11.4, −4.86, −4.89.

(3α,5α)-13-Acetyl-3-hydroxy-18-norpregnan-20-one (65, ZYC-71)

Compound 64 (70 mg, 0.15 mmol) was dissolved in acetone (20 mL),sulfuric acid (18 N, 0.1 mL) was added and the reaction stirred at roomtemperature. After 1 hr, additional sulfuric acid was added (18 N, 0.15mL) and after 2 h sulfuric acid (18 N, 0.1 mL) was again added. After2.5 h, approximately 50% of the solvent was removed and saturatedaqueous NaHCO₃ (1 mL) was added. Water was added and the productextracted into EtOAc. The EtOAc was washed with brine, dried and removedto give crude product (50 mg). Purification by flash chromatography(silica gel eluted with 40-50% EtOAc in hexanes) gave compound 65 (40mg) which contained a trace amount of the 20α-epimer that was removed byrecrystallization from CH₂Cl₂/hexanes. Compound 65 (24 mg) was obtainedas a white solid: mp 180-181° C.; IR v_(max) 3442, 2928, 2858, 1696,1445, 1430 cm⁻¹; ¹H NMR (CDCl₃) δ 4.04 (m, 1H), 2.75-2.64 (m, 2H), 2.17(s, 3H), 2.08 (s, 3H), 1.59 (s, 3H), 0.69 (s, 3H); ¹³C NMR (CDCl₃) δ211.8, 209.0, 66.3, 64.2, 61.6, 57.8, 54.5, 39.0, 36.2, 36.08, 35.96,35.8, 32.1, 31.8, 30.8, 30.1, 28.9, 28.2, 25.5, 24.8, 22.8, 11.2. Anal.(C₂₂H₃₄O₃): C, 76.26; H, 9.89. Found: C, 76.40; H, 9.76.

In accordance with Scheme 7, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3α,5α,20R)-13-Acetyl-18-norpregnane-3,20-diol (66, ZYC-72)

Compound 60 (120 mg) was converted to compound 66 using the proceduredescribed for the preparation of compound 54. Compound 66 (50 mg) had:mp 159-161° C.; IR v_(max) 3430, 2915, 1676 cm⁻¹; ¹H NMR (CD₃OD) δ 3.94(m, 1H), 3.34 (m, 1H), 2.89 (dm, 1H, J=3.7 Hz), 2.30 (d, 1H, J=1.3 Hz),1.11 (d, 3H, J=2.2 Hz), 0.70 (s, 3H); ¹³C NMR (THF-d₅) δ 213.6, 70.4,62.6, 60.2, 59.1, 56.1, 40.1, 38.1, 37.5, 37.4, 37.1, 33.4, 33.3, 30.2,29.8, 27.6, 24.9, 26.0, 24.9, 24.7, 24.2, 11.9. Anal. (C₂₂H₃₆O₃): C,75.82; H, 10.41. Found: C, 76.01; H, 10.50.

In accordance with Scheme 8, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3α,5α,20R)-18,20-epoxy-Pregnane-3,18-diol (67)

Compound 59 (610 mg, 1.68 mmol) was dissolved in cyclohexane and stirredunder N₂. CaCO₃ (680 mg), Pb(OAc)₄ (4.12 g), and I₂ (1.06 g) wereirradiated with a high intensity tungsten lamp for 130 min. The solventrefluxed during irradiation. The reaction was allowed to cool to roomtemperature, filtered and the cyclohexane solution washed with 10%aqueous Na₂S₂O₃, brine and dried. Solvent removal gave an oil (1.07 g).Purification by flash column chromatography (silica gel eluted with5-30% EtOAc in hexanes) gave compound 67 (272 mg) as a mixture ofepimeric 18,20-epoxy compounds. The epimeric mixture had: IR v_(max)3469, 2934, 2858, 1736, 1446, 1375, 1362, 1235; a partial list ofresonances consistent with the assigned structure is as follows: ¹H NMR(CDCl₃) δ 6.20 (s), 6.05 (s), 5.00 (m), 4.39-4.33 (m), 4.21-4.01), 2.077(s), 2.076 (s), 2.08 (s), 2.07 (s), 2.05 (s), 0.74 (s), 0.69 (s); ¹³CNMR 170.7, 170.1, 102.0, 100.5, 85.7, 84.2, 82.4, 70.1, 70.0, 58.9,57.1, 56.9, 56.2, 55.0, 54.9, 54.7, 54.6, 53.5, 53.4, 50.7.

(3α,5α,20R)-13-Isopropenyl-18-norpregnan-3,20-diol, 3-acetate (68)

CH₃PPh₃Br (1.52 g, 4.25 mmol) and KOBu^(t) (480 mg, 4.28 mmol) werestirred in THF (25 mL) at room temperature for 30 min. Compound 67 (124mg, 0.33 mmol) dissolved in THF (5 mL) was added and stirring at roomtemperature continued for 15 min, at reflux for 4.75 h and overnight atroom temperature. The solvent was removed, water added and the productextracted into EtOAc. The EtOAc was washed with brine, dried and removedto yield an oily solid. Purification by flash column chromatography(silica gel eluted with 5-35% EtOAc in hexanes) gave compound 68 (25mg): IR v_(max) 3473, 2948, 2921, 2866, 2841, 1727, 1446, 1375, 1270cm⁻¹; ¹H NMR δ 5.66 (dd, 1H J=11.3 Hz, J=17 Hz), 5.32 (dd, 1H, J=1.6 Hz,J=11 Hz), 5.19 (dd, 1H, J=1.6 Hz, J=18.7 Hz), 5.00 (b s, 1H), 3.61 (m,1H), 2.50 (dm, 1H, J=13 Hz), 2.05 (s, 3H), 1.10 (d, 3H, J=6.3 Hz), 0.71(s, 3H); ¹³C NMR δ 170.6, 138.3, 115.9, 70.7, 70.1, 58.9, 56.8, 54.7,50.3, 40.4, 36.3, 35.8, 32.9, 31.8, 28.2, 26.1, 25.8, 24.1, 22.7, 21.5,20.9, 11.3.

(3α,5α)-3-Hydroxy-13-isopropenyl-18-norpregnan-20-one, 3-acetate (69)

Compound 68 (31 mg, mmol) was dissolved in acetone (1.5 mL) and cooledto −5° C. Jones reagent (0.1 mL) was added and stirring continued for 45min. 2-Propanol (a few drops) was added and stirring continued for 15min. The solvent was removed and the crude product purified by flashcolumn chromatography (silica gel eluted with 25% EtOAc in hexanes) togive compound 69 (23 mg): ¹H NMR (CDCl₃) δ 5.57 (dd, 1H, J=11.3 Hz,J=17.9 Hz), 5.18 (d, 1H, J=11.2 Hz), 5.01-4.95 (m, 2H), 2.65-2.51 (m,2H), 2.21 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 0.72 (s, 3H); ¹³C NMR(CDCl₃) δ 208.3, 170.6, 136.5, 116.0, 70.0, 64.8, 57.5, 54.4, 51.1,39.9, 36.4, 35.8, 34.9, 32.9, 32.8, 31.7, 31.0, 28.1, 26.1, 23.9, 22.8,21.5, 21.1, 11.3.

(3α,5α)-3-Hydroxy-13-isopropenyl-18-norpregnan-20-one (70, ZYC-75)

Compound 69 (23 mg) in aqueous MeOH containing Na₂CO₃ (3 mL of asolution containing 250 mg Na₂CO₃ in 1.3 ml water and 11.7 mL MeOH) washeated to reflux, cooled and the solvent removed. The product waspurified by flash column chromatography (silica gel eluted with 5-60%EtOAc in hexanes) to give compound 70 (17 mg) as a white solid: mp146-147° C.; IR v_(max) 3304, 2929, 2876, 2852, 1712, 1636, 1450 cm⁻¹;¹H NMR (CDCl₃) δ 5.56 (dd, 1H, J=11.3 Hz, J=17.9 Hz), 5.18 (dd, 1H,J=1.1 Hz, J=11.3 Hz), 4.98 (dd, 1H, J=1.5 Hz, J=17.8 Hz), 4.04 (m, 1H),2.62-2.50 (m, 2H), 2.25-2.13 (m, 1H), 2.06 (s, 3H), 0.70 (3H); ¹³C NMR(CDCl₃) δ 208.3, 136.6, 115.9, 66.5, 64.8, 57.6, 54.6, 51.2, 39.1, 36.4,36.1, 35.9, 34.9, 32.2, 31.8, 31.0, 29.0, 28.3, 23.9, 22.8, 21.1, 11.2.Anal. (C₂₂H₃₄O₂): C, 79.95; H, 10.37. Found: C, 79.86; H, 10.16.

In accordance with Scheme 9, the following compounds were prepared,using methods generally known in the art and as outlined below.

1-[(3α,5α,17β)-3-Hydroxy-17-hydroxymethyl-18-norandrostan-13-yl]ethanone(71, ZYC-73)

Compound 71 (17 mg, 68%) was prepared from compound 54 using theprocedure described for the preparation of compound 57 from compound 56.Compound 71 was a white solid: mp 166-168° C.; IR v_(max) 3339, 2929,2861, 1696, 1445 cm⁻¹; ¹H NMR (acetone-d₆) δ 3.93 (m, 1H), 3.75 (dd, 1H,J=4.2 Hz, J=4.5 Hz), 3.54-3.46 (m, 2H), 3.30 (d, 1H, J=3 Hz), 2.76 (dm,1H, J=13.7), 2.20 (s, 3H), 0.68 (s, 3H); ¹³C NMR (acetone-d₆) 213.25,66.0, 63.7, 61.7, 58.7, 56.0, 54.1, 39.8, 37.1, 37.0, 39.9, 33.2, 33.0,30.7, 30.2, 29.8, 26.6, 25.7, 23.8, 11.8. Anal. (C₂₁H₃₄O₃): C, 75.41; H,10.25. Found: C, 74.95; H, 9.95.

1-[(3α,5α,17β)-17-Chloromethyl-3-(methoxymethoxy)-18-norandrostan-13-yl]ethanone(72)

Compound 71 (78 mg, 0.21 mmol) and Et₃N (0.035 mL, 0.25 mmol) weredissolved in CH₂Cl₂ and cooled to 0° C. CH₃SO₂Cl (0.025 mL, 0.32 mL) wasadded and stirring continued overnight in a cold room maintained ataround 4° C. Water was added and the product was extracted into CH₂Cl₂.The CH₂Cl₂ was washed with brine, dried and removed to yield the crudeproduct as crystals in a brown oil. Purification by flash columnchromatography (silica gel eluted with 5-15% EtOAc in hexanes) gavecompound 72 (20 mg, 25%): IR v_(max) 2935, 2876, 2836, 1688, 1447, 1357,1214 cm⁻¹; ¹H NMR δ 4.65 (m, 2H), 3.82 (m, 1H), 3.51 (dd, 1H, J=7.7 Hz,J=11 Hz), 3.41-3.35 (overlapped m, 1H), 3.37 (s, 3H), 2.70 (dt, 1H,J=13.4 Hz, J=3 Hz), 2.21 (s, 3H), 0.68 (s, 3H); ¹³C NMR δ 212.5, 94.6,71.6, 61.7, 57.9, 55.1, 54.7, 52.9, 45.7, 39.8, 36.4, 35.9, 33.6, 32.9,31.8, 30.4, 28.4, 26.4, 24.8, 23.0, 11.5.

1-[(3α,5α,17β)-17-Chloromethyl-3-hydroxy-18-norandrostan-13-yl]ethanone(73, ZYC-74)

Compound 73 (13 mg, %) was prepared from compound 72 using the proceduredescribed for the preparation of compound 57 from compound 56. Compound73 was a white solid: mp 161-162° C.; IR v_(max) 3306, 2929, 2861, 1695,1445 cm⁻¹; ¹H NMR (CDCl₃) δ 4.04 (m, 1H), 3.51 (dd, 1H, J=7.7 Hz, J=10.8Hz), 3.38 (dd, 1H, J=7.4 Hz, J=10.8 Hz), 2.72 (dm, 1H, J=13.4 Hz), 2.21(s, 3H), 0.68 (s, 3H); ¹³C NMR (CDCl₃) δ 212.8, 66.4, 61.6, 57.8, 54.6,52.8, 45.7, 39.1, 36.3, 36.0, 35.8, 32.1, 31.8, 30.4, 28.9, 28.3, 28.2,24.7, 22.9, 11.2. HRMS (EI) Calcd for (C₂₁H₃₃ClO₂): 352.2169 (³⁵Clisotope). Found 352.2170.

In accordance with Scheme 10, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3α,5α,20R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-pregnan-20-ol (74)

The commercially available steroid (3α,5α)-3-hydroxypregnan-2-one (1 g,3.14 mmol) was dissolved in stirred CH₂Cl₂ (20 mL) andmethoxymethychloride (0.75 mL) was added. The reaction was cooled to 0°C. and diisopropylethylamine (2.6 mL) was added and stirring wascontinued at 0° C. for 1.5 h and then at room temperature overnight.Aqueous NH₄Cl was added and the product extracted into CH₂Cl₂. TheCH₂Cl₂ was washed with brine, dried and the solvent removed. The crudeproduct (1.58 g) was purified by flash column chromatography (silica geleluted with 20% EtOAc in hexanes to give the intermediate(3α,5α)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-pregnan-20-one (1.01g) which was reduced to a mixture of the 20R and 20S alcohols by NaBH₄(added in four portions) in MeOH (30 mL) and THF (10 mL) at −5° C. to 0°C. The reaction time was 1 h. The solvent was removed, water was addedand the product extracted into EtOAc. The EtOAc was dried and removedand the 20R and 20S alcohols (˜4:1 ratio, 1 g) were purified andseparated by flash column chromatography (silica gel eluted with 5-30%EtOAc in hexanes) to give pure product 74 (0.84 g) as a white solidwhich had: ¹H NMR (CDCl₃) δ 4.66 (m, 2H), 3.82 (m, 1H), 3.72 (m, 1H),3.37 (s, 3H), 2.03 (m, 1H), 1.12 (d, 3H, J=6.3 Hz), 0.79 (s, 3H), 0.74(s, 3H).

(3α,5α,20R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-18,20-epoxy-Pregnan-18-ol(75)

Compound 75 (240 mg crude containing compound 74) was prepared fromcompound 74 using the procedure described for the preparation ofcompound 67 from compound 59. Compound 75 was not characterized.

(3α,5α)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-13-ethenyl-18-norpregnan-20-ol(76)

Compound 76 (29 mg) was prepared from compound 75 using the proceduredescribed for the preparation of compound 68 from compound 67. Compound76 was a crystalline solid: ¹H MNR (CDCl₃) δ 5.66 (dd, 1H, J=11.5 Hz,J=12.7 Hz), 5.33-5.16 (m, 2H), 4.65 (m, 2H), 3.81 (m, 1H), 3.60 (m, 1H),3.36 (s, 3H), 2.50 (dm, 1H, J=12.6 Hz), 1.09 (d, 1H, J=6.3 Hz), 0.71 (s,3H); ¹³C NMR (CDCl₃) δ 138.2, 115.7, 94.3, 71.5, 70.6, 58.6, 56.7, 55.0,54.6, 50.1, 39.5, 36.2, 35.7, 35.6, 33.5, 32.7, 31.7, 28.3, 26.1, 25.6,23.9, 22.6, 20.7, 11.3.

(3α,5α,20R)-13-Ethenyl-18-norpregnan-3,20-diol (77, ZYC-76)

Compound 77 (19 mg, 76%) was prepared from compound 76 using theprocedure described for the preparation of compound 57 from compound 56.Compound 77 was a white solid: mp 193-195° C.; IR v_(max) 3369, 2921,2873, 1633, 1445 cm⁻¹; ¹H NMR (CDCl₃) δ 5.64 (dd, 1H, J=11.2 Hz, J=17.9Hz), 5.32 (dd, 1H, J=1.9 Hz, J=11.3 Hz), 5.19 (dd, 1H, J=1.7 Hz, J=17.9Hz), 4.03 (m, 1H), 3.61 (m, 1H), 2.48 (dt, 1H; J=2.7 Hz, J=12.7 Hz),1.09 (d, 3H, J=6.3 Hz), 0.70 (s, 3H); ¹³C NMR (CDCl₃) δ 138.2, 115.8,70.7, 66.5, 58.7, 56.7, 54.6, 50.1, 39.0, 36.2, 36.0, 35.8, 35.6, 32.1,31.8, 29.0, 28.3, 25.7, 24.0, 22.6, 20.8, 11.2. Anal. (C₂₂H₃₆O₂): C,79.46; H, 10.91. Found: C, 79.54; H, 10.79.

[³⁵S]-TBPS Displacement

The IC₆₀ values for non-competitive displacers of [³⁵S]-TBPS from thepicrotoxin binding site on GABA_(A) receptors are reported in Table 1.

TABLE 1 Inhibition of [³⁵S]-TBPS Binding Compound IC₅₀ (nM) n_(Hill)KK-140 17 ± 3  0.79 ± 0.07 KK-143 270 ± 19  1.14 ± 0.08 KK-144 72 ± 161.31 ± 0.32 KK-145 53 ± 4  1.21 ± 0.10 XJ-99 43 ± 12 1.43 ± 0.44 XJ-100276 ± 130 0.78 ± 0.24 ZYC-71 82 ± 7  1.11 ± 0.08 ZYC-72 978 ± 618 0.70 ±0.24 ZYC-73 1,460 ± 270   1.02 ± 0.13 ZYC-74 415 ± 83  1.02 ± 0.17ZYC-75 27 ± 5  1.02 ± 0.15 ZYC-76 497 ± 59  1.50 ± 0.21

Results presented are from duplicate experiments performed intriplicate. Error limits are calculated as standard error of the mean.Methods used are known in the art (see Jiang, X., et al., Neurosteroidanalogues. 9. Conformationally constrained pregnanes: structure-activitystudies of 13,24-cyclo-18,21-dinorcholane analogues of the GABAmodulatory and anesthetic steroids (3α,5α)- and(3α,5α)-3-hydroxypregnan-20-one. J. Med. Chem., 46: 5334-48 (2003)—thecontents of which are hereby incorporated by reference in theirentirety).

Electrophysiology Results

The compounds of the present disclosure were evaluated for the abilityto potentiate chloride currents mediated by 2 μM GABA at rat α₁β₂γ_(2L)type GABA_(A) receptors expressed in Xenopus laevis oocytes and theresults are shown in Table 2.

TABLE 2 Analogue Potentiation of GABA Effects at Rat α1β2γ2GABA_(A)Receptors Expressed in Frog Oocytes oocyte electrophysiology^(a)Compound 0.1 μM 1 μM 10 μM (gating) 10 μM KK-140 5.39 ± 2.76 11.90 ±1.08  17.29 ± 2.10  0.27 ± 0.06 KK-143 1.23 ± 0.06 2.93 ± 0.30 8.43 ±0.69 0.07 ± 0.02 KK-144 1.40 ± 0.11 5.38 ± 0.55 10.59 ± 1.31  0.18 ±0.02 KK-145 1.75 ± 0.14 13.74 ± 3.71  35.57 ± 12.85 0.56 ± 0.07 XJ-991.73 ± 0.20 3.96 ± 0.99 4.37 ± 1.28 0.07 ± 0.02 XJ-100 1.33 ± 0.20 5.01± 0.89 8.41 ± 0.66 −0.06 ± 0.06   ZYC-71 1.82 ± 0.03 9.31 ± 0.46 19.44 ±1.69  0.22 ± 0.01 ZYC-72 0.80 ± 0.08 1.30 ± 0.11 2.78 ± 0.37 −0.03 ±0.11   ZYC-73 1.07 ± 0.15 1.42 ± 0.16 6.16 ± 0.71  

 −0.09 ± 0.09 ZYC-74 1.06 ± 0.04 1.98 ± 0.21 9.38 ± 1.71 0.03 ± 0.01ZYC-75 1.93 ± 0.18 7.07 ± 1.89 12.02 ± 3.53  0.20 ± 0.05 ZYC-76 1.00 ±0.01 1.56 ± 0.13 7.28 ± 1.76 0.04 ± 0.02

^(a)The GABA concentration used for the control response was 2 μM. Eachcompound was evaluated on at least four different oocytes at theconcentrations indicated, and the results reported are the ratio ofcurrents measured in the presence/absence of added compound. Gatingrepresents direct current gated by 10 μM compound in the absence ofGABA, and this current is reported as the ratio of compound onlycurrent/2 μM GABA current. Error limits are calculated as standard errorof the mean (N≧4). Methods used are known in the art (see Jiang, X., etal.).

Tadpole Loss of Righting and Swimming

Table 3 discloses the anesthetic effects of the compounds of the presentdisclosure. In particular, the anesthetic effect of the compounds of thepresent disclosure on Loss of Righting Reflex (LRR) and Loss of SwimmingReflex (LSR).

TABLE 3 Tadpole Loss of Righting (LRR) & Loss of Swimming (LSR) EC₅₀Values (μM) Reflexes by Analogues Tadpole Tadpole Tadpole LRR LRR LSRTadpole LSR Compound EC₅₀ (μM) n_(Hill) EC₅₀ (μM) n_(Hill) KK-140 0.05 ±0   −1.80 ± 0.10 0.30 ± 0   −3.5 ± 0.3 KK-143 0.61 ± 0.06 −1.80 ± 0.271.73 ± 0.03 −36.3 ± 0.1  KK-144 0.18 ± 0.01 −2.25 ± 0.15 0.55 ± 0.01−33.3 ± 0.1  KK-145 0.14 ± 0.01 −2.55 ± 0.42 0.55 ± 0.01 −33.3 ± 0.1 XJ-99 0.05 ± 0.00 −2.90 ± 0.05 0.14 ± 0.0  −3.95 ± 0.02 XJ-100 0.46 ±0.16 −1.23 ± 0.44 >10 — ZYC-71 1.73 ± 0.01 −4.00 ± 0.02 5.48 ± 0.15−33.5 ± 0.1  ZYC-72 3.06 ± 0.00 −21.3 ± 0.0  >10 — ZYC-73 >10 — None —ZYC-74 3.33 ± 1.41 −2.36 ± 2.35 5.48 ± 0.20 −33.2 ± 0.2  ZYC-75 0.67 ±0.01 −2.26 ± 0.22 2.64 ± 0.01 −22.8 ± 0.7  ZYC-76 742 ± 202 −1.64 ± 0.581.74 ± 0.03 −35.9 ± 0.1 

Methods used are known in the art (see Jiang, X., et al.). Error limitsare calculated as standard error of the mean (N=10 or more animals ateach of five or more different concentrations).

General Methods

The compounds discussed in the present disclosure were produced asdiscussed elsewhere throughout this disclosure and by the followingmethods.

Solvents were either used as purchased or dried and purified by standardmethodology. Extraction solvents were dried with anhydrous Na₂SO₄ andafter filtration, removed on a rotary evaporator. Flash chromatographywas performed using silica gel (32-63 μm) purchased from ScientificAdsorbents (Atlanta, Ga.). Melting points were determined on a Koflermicro hot stage and are uncorrected. FT-IR spectra were recorded asfilms on a NaCl plate. NMR spectra were recorded in CDCl₃ at ambienttemperature at 300 MHz (¹H) or 74 MHz (¹³C). Purity was determined byTLC on 250 μm thick Uniplates™ from Analtech (Newark, Del.). All purecompounds (purity >95%) gave a single spot on TLC. Elemental analyseswere performed by M-H-W Laboratories (Phoenix, Ariz.).

EQUIVALENTS AND SCOPE

In view of the above, it will be seen that the several advantages of thedisclosure are achieved and other advantageous results attained. Asvarious changes could be made in the above processes and compositeswithout departing from the scope of the disclosure, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

When introducing elements of the present disclosure or the variousversions, embodiment(s) or aspects thereof, the articles “a”, “an”,“the” and “said” are intended to mean that there are one or more of theelements. It is also noted that the terms “comprising”, “including”,“having” or “containing” are intended to be open and permits theinclusion of additional elements or steps.

What is claimed is:
 1. A method of inducing anesthesia in a subject inneed thereof, the method comprising administering to the subject atherapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R₁ is H,optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl; R₂ is H, optionallysubstituted C₁-C₄ alkoxy, aryloxy, optionally substituted C₂-C₄alkenoxy, optionally substituted C₂-C₄ alkynoxy, or —O—C(O)—R_(x), whereR_(x) is optionally substituted C₁-C₂₀ alkyl; R₃ is H, optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl,optionally substituted alkynyl, cyclopropyl, or C(O)R_(y), where R_(y)is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl; R₄ is optionallysubstituted C₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl,optionally substituted cyclopropyl, or C(O)R_(z), where R_(z) is C₁-C₄alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl; R₅ is H, ═O, or OR_(v), whereR_(v) is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, optionally substituted C₂-C₄ alkynyl, or optionallysubstituted aryl; R₆ is H, optionally substituted C₁-C₄ alkyl,optionally substituted C₂-C₄ alkenyl, or optionally substituted C₂-C₄alkynyl; R₇ is H, optionally substituted C₁-C₄ alkoxy, aryloxy,morpholinyl, optionally substituted C₂-C₄ alkenoxy, optionallysubstituted C₂-C₄ alkynoxy, or —O—C(O)—R_(w), where R_(w), is optionallysubstituted C₁-C₂₀ alkyl; R₈ is, when present, H, C₁-C₄ alkyl, C₂-C₄alkenyl, or C₂-C₄ alkynyl; R₉ is H or C(O)R_(u), where R_(u) isoptionally substituted C₁-C₂₀ alkyl, optionally substituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀ alkynyl; wherein the C₅—H isin the alpha configuration; and, - - - denotes an optional, additionalC—C bond, resulting in either a C═C bond between C₄-C₅ or C₅-C₆, withthe proviso that when present, the C₅—H substituent is not present. 2.The method of claim 1, wherein R₉ is H.
 3. The method of claim 1,wherein R₂ is H or —OCH₃.
 4. The method of claim 1, wherein R₅ is H or—OCH₃.
 5. The method of claim 1, wherein R₆ is methyl or —CH₂OCH₃. 6.The method of claim 1, wherein R₇ is H or —OCH₃.
 7. The method of claim1, wherein R₄ is —CH═CH₂ or —C(O)CH₃.
 8. The method of claim 1, whereinR₃ is selected from the group consisting of —CH═CH₂, ethyl, —C(O)CH₃,hydroxy alkyl, and haloalkyl.
 9. The method of claim 8, wherein R₃ ishydroxy alkyl.
 10. The method of claim 8, wherein R₃ is —CH₂Cl.
 11. Themethod of claim 8, wherein R₃ is selected from the group consisting—C(OH)CH₃ and —CH₂(OH).
 12. The method of claim 1, wherein R₁ is H. 13.The method of claim 1, wherein the compound is of the structure:

wherein R₃ is H, optionally substituted C₁-C₄ alkyl, optionallysubstituted C₂-C₄ alkenyl, optionally substituted alkynyl, cyclopropyl,or C(O)R_(y), where R_(y) is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄alkynyl; and, R₄ is optionally substituted C₂-C₄ alkenyl, optionallysubstituted C₂-C₄ alkynyl, optionally substituted cyclopropyl, orC(O)R_(z), where R_(z) is C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl.14. The method of claim 1, wherein the compound is of the structureselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticallyacceptable salt of a compound of the method of claim
 1. 16. Apharmaceutical composition comprising a compound of the method of claim1, a pharmaceutically acceptable salt thereof, or a combination of twoor more thereof, and a pharmaceutically acceptable carrier.